WO2016024844A1 - Oral combined preparation containing omega-3 fatty ester and statin-based drug - Google Patents

Abstract

The present invention relates to a pharmaceutical combined preparation containing an omega-3 fatty ester and a statin-based drug. The oral combined preparation according to the present invention contains, a tablet containing a statin-based drug, inside a capsule agent containing an omega-3 fatty acid ester, and thus, the oral combined preparation is fundamentally and completely cut off from contact with an external environment, including moisture, low pH, and the like, thereby showing high stability and excellent disintegration and dissolution rates.

Description

Oral combinations containing omega-3 fatty acid esters and statins

The present invention relates to a co-formulation comprising an omega-3 fatty acid ester and a statin drug.

Omega-3 fatty acid esters play a role in lowering serum triglycerides (TG), lowering systolic and diastolic blood pressure and pulse rate without causing any side effects, and lowering the activity of blood coagulation factor 일으키 phospholipid complexes.

Statin-based drugs are known to reduce the risk of coronary heart disease (CHD) to about one third, but have limited effects on TG and serum high density lipoprotein (HDL).

Therefore, a combination drug of HMG-CoA reductase inhibitor and omega-3 fatty acid ester in hypercholesterolemia patients requiring blood triglyceride level control has the advantage of effectively lowering blood cholesterol level and triglyceride level simultaneously. Accordingly, various attempts have been made to prepare combination formulations of two drugs.

For example, ① Korean Patent Publication No. 10-2012-109950 discloses an oral complex composition comprising an omega-3 fatty acid ester and an HMG-CoA reductase inhibitor and a preparation method thereof, and (ii) Korean Patent Publication 10-2013-104059 discloses an omega-3 fatty acid inner layer; Water-soluble polymer interlayers; And an outer layer of an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof.

In addition, US Patent Publication No. 2013/0115281 discloses multiple soft gelatin formulations in which a soft gelatin formulation comprising a solid formulation comprising a pretreated statin drug and a soft gelatin formulation comprising an omega-3 fatty acid ester are attached. Is disclosed.

However, the invention disclosed in the documents of ① and ② is uniformly applied to the outer layer containing the omega-3, the statin-based drug is very large surface area compared to the general tablets, and thus, due to the external environment such as moisture, low pH Due to the interaction of the formulation, which can cause a decrease in stability, a decrease in content and an increase in the softening material, it is very difficult to adjust the dissolution pattern of statin-based drugs, and there is a high possibility of problems in content uniformity.

In the case of the invention disclosed in the above ③, there is a problem that the statin-based drug may have an interaction with external moisture and air, which may cause a decrease in stability, a decrease in content, and an increase in softening material.

Accordingly, the inventors of the present invention, while studying a combination formulation of a statin-based drug and omega-3, have completed the present invention by developing a formulation that can overcome the disadvantages of the preceding invention.

An object of the present invention is a combination preparation containing an omega-3 fatty acid ester and a statin-based drug, a combination formulation that is highly stable, can suppress the increase of the flexible material, and can prevent the decrease in the content of the statin-based drug To provide.

Another object of the present invention is to provide a co-formulation comprising an omega-3 fatty acid ester and a statin-based drug having excellent disintegration rate and dissolution rate.

According to one aspect, the present invention provides an omega-3 fatty acid ester-containing capsule; And it provides an oral combination formulation having a statin-based drug-containing tablets contained in the capsule.

In the combination preparation, the statin-based drug-containing tablet may further include a disintegrant, and the statin-based drug-containing tablet may be a tablet coated with a film coating base.

In one embodiment, the shell of the capsule is arivaba gum, tracacanta gum, karaya gum, katty gum, guar gum, loggers Kong gum, tara gum, konjac gum, algin, agar, carrageenan, flulan, pectin, gellan, It may be composed of at least one component selected from the group consisting of mannan, glycerin, gelatin and xanthan gum.

In another embodiment, the statin-based drug contained in the co-formulation is 70 to 85% by weight based on the total weight of the co-formulation in 30 minutes to 1 hour under the conditions according to the general paddle method, or the rotational sample method According to the conditions may be an oral combination preparation that elutes 70 to 85% by weight based on the total weight of the combination preparation in 30 minutes to 1 hour.

The oral combination preparation according to the present invention includes an omega-3 fatty acid ester-containing capsule and a statin-based drug-containing tablet embedded in the capsule, so that the statin-based drug-containing tablet is essentially water, low pH. Since the contact with the external environment is completely blocked, there is an advantage of showing high stability.

In addition, the oral combination preparation of the present invention exhibits a high disintegration rate and dissolution rate even though a tablet containing a statin-based drug is contained in the capsule, and furthermore, it disintegrates and dissolves within an appropriate time range, The drug may not be exposed to stomach acid.

In addition, it is possible to see the statin-based drug-containing tablets are encapsulated inside the capsule from the outside with the transparency of the capsule shell, thereby making the consumer more reliable, such as psychological and advertising effects.

1 is a view showing the excellent dissolution rate of the oral combination preparation of the present invention.

Figure 2 is a view showing a photograph of the oral combination preparation prepared according to Example 1.

Hereinafter, the present invention will be described in detail.

The present invention is an omega-3 fatty acid ester-containing capsule; And it relates to oral combinations having a statin-based drug-containing tablets contained in the capsule, in one embodiment the combination may be a pharmaceutical combination.

In the present invention, "capsule" means that the drug or drug is packed into capsules or manufactured by capsules, and "tablet" means that the drug or drug is compressed to a certain shape by adding an appropriate additive to the drug or drug. .

Omega-3 fatty acid esters may play a role in lowering serum triglycerides (TGs), lowering systolic and diastolic blood pressure and pulse rate, and lowering the activity of the blood coagulation factor phospholipid complex with little side effects in the human body.

As used herein, "omega-3 fatty acids" are omega-3 unsaturated fatty acids (ω-3 unsaturated fatty acids), omega-3 highly unsaturated fatty acids, polyunsaturated fatty acids (PUFA) Docosahexaenoic acid (DHA), eicosapentaenoic aicd (EPA), arachidonic acid (ARA), docosapentaenoic acid (Docosapentaenoic aicd) , α-linolenic acid, mixtures thereof, and the like. In one embodiment, the omega-3 fatty acid ester may be an omega-3 fatty acid alkyl ester.

Statin drugs can reduce cholesterol by slowing the production of cholesterol by inhibiting HMG-CoA reductase, which regulates the body's cholesterol production rate, or by increasing the liver's ability to remove LDL cholesterol already present in the blood. In other words, the main effect of statin drugs is to lower LDL cholesterol.

Statin-based drugs are known to reduce the risk of coronary heart disease (CHD) to about one third, but have limited effects on TG and serum high density lipoprotein (HDL).

Patients with hypercholesterolemia and combined dyslipidemia have elevated levels of both LDL and TG. Therefore, the combination of omega-3 fatty acid esters and statins may be effective when combined with high LDL and triglyceride levels. It is obvious.

Therefore, oral combination formulations combining omega-3 fatty acid esters and statin drugs may not only provide excellent effects as described above, but may also relieve the discomfort of patients having to take two drugs, thereby increasing medication compliance. There is also an advantage.

However, co-formulations containing two or more active ingredients have the potential for two drugs to interact with each other, and the dissolution or disintegration of some of the components may be caused by other ingredients. It is not easy for a person skilled in the art.

For example, a formulation containing an omega-3 fatty acid ester is present in the core portion of the co-formulation and a statin-based drug is placed on the surface of the core portion. Since the surface of the core portion must be applied, the surface area becomes much larger than that of ordinary tablets.

Instability due to the external environment (such as moisture, low pH due to air containing CO ₂ ) of statin drugs is well known in the art. As the surface of the statin-based drug contacts the air due to the external environmental factors, problems such as stability and content of the statin-based drug in the pharmaceutical formulation and increase in the softening material may appear. In the case of medicines, there is a problem that cannot be used industrially because they cannot be marketed without permission of the permitting authority due to these problems.

In addition, in the case of the above formulation, since the statin-based drug is disposed on the surface of the core portion, it is very difficult to adjust the dissolution pattern, and there is a high possibility of problems in content uniformity. Therefore, there is a problem that the development cost is increased because a large number of trial and error of a person skilled in the art for the completion of such a formulation.

In addition, for example, a case of a soft gelatin formulation including a solid formulation including a statin-based drug and a multiple soft gelatin formulation attached to a soft gelatin formulation including an omega-3 fatty acid ester may be assumed. .

Even in this case, the statin-based drug may interact with external moisture and air, and thus, it may not solve the problems of deterioration in stability, content decrease, and increase in softening material of the statin-based drug.

In the case of the co-formulation of the present invention, the capsule containing the omega-3 fatty acid ester has a structure in which a tablet containing a statin-based drug is infiltrated into the capsule. Since the tablet is encapsulated inside the capsule and the external water and air cannot pass through the capsule layer containing the lipophilic omega-3 fatty acid ester, the statin-based drugs included in the tablet are water, air, etc. Contact with the external environment is fundamentally blocked, which makes statin drugs stable for a long time.

In one embodiment, the present invention provides an omega-3 fatty acid ester-containing capsule; And a tablet containing a statin-based drug (eg, atorvastatin or rosuvastatin) embedded in the capsule, for a long period of storage at various temperature and humidity conditions. It was confirmed that the combination formulation showed excellent stability through no change in the statin-based drug content.

In another embodiment, omega-3 fatty acid ester-containing capsules; And a tablet containing a statin-based drug (eg, atorvastatin or rosuvastatin) contained within the capsule, the capsule may be completely disintegrated within 30 minutes when the release experiment is performed. Could.

In addition, in the case of dissolution experiment (rotational sample method or general paddle method) using the co-formulation, the statin-based drug of about 70-85 wt% or more of the total weight of the co-formulation could be eluted within 30 minutes to 1 hour. . In one embodiment, the dissolution experiment eluted about 70-85% by weight of the statin-based drug of the total weight of the co-formulation within 30 minutes to 1 hour at 50-150 rpm.

That is, since the co-formulation disintegrates and / or elutes within an appropriate time range, the co-formulation disintegrates and / or elutes too quickly, thereby preventing the problem of statin-based drugs from being exposed to the acid located above.

In addition, the formulation structure of the oral combination preparation of the present invention does not have any negative effect on the effective and effective effects of the omega-3 fatty acid esters and statin-based drugs in the body.

In one embodiment, the omega-3 fatty acid ester contained in the oral co-formulation of the present invention is preferably 30 to 80% by weight based on the total weight of the oral co-formulation.

If the omega-3 fatty acid ester is less than 30% by weight based on the total weight of the oral co-formulation, there is a disadvantage in that sufficient therapeutic effect is not obtained, and in the case of more than 80% by weight, the convenience of taking due to the increased size of the manufactured soft capsule There is a downside to falling.

In one embodiment, the statin-based drug included in the oral co-formulation of the present invention is preferably 0.5 to 10% by weight based on the total weight of the oral co-formulation.

If the statin-based drug is less than 0.5% by weight based on the total weight of the oral combination formulation, there is a disadvantage in that sufficient therapeutic effect is not obtained. If the statin-based drug is more than 10% by weight, side effects may occur due to the overdose of the drug.

Statin-based drugs included in the oral combination formulation of the present invention include atorvastatin, rosuvastatin, lovastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and fluvastatin. At least one member selected from the group consisting of pharmaceutically acceptable salts thereof.

As used herein, "pharmaceutically acceptable salts" refers to salts prepared according to conventional methods in the art, and methods for preparing such salts are known to those skilled in the art.

Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.

Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.

Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.

Statin-based drug-containing tablet of the present invention may be in the form of a film coated tablet coated with a film coating base, the film coating base is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and polyvinylacetate It may include more than one species. In one embodiment, the film coating base may use Opadry® including Opadry White, Opadry Pink, Opadry Green, Opadry Orange, Opadry Blue, Opadry Yellow, Opadry Brown, and the like. have.

As described above, the interaction between the two drugs may be a problem when preparing an oral combination preparation including a statin-based drug and an omega-3 fatty acid ester. Therefore, the oral combination preparation of the present invention has a structure in which a tablet containing a statin-based drug is embedded in a capsule containing an omega-3 fatty acid ester, thereby preventing interaction between the two drugs. .

Tablets containing a statin-based drug of the oral combination preparation of the present invention include a pharmaceutically acceptable excipient, a binder, a disintegrant, a disintegration accelerator, a lubricant, a coating agent, a film coating base, an enteric film coating base, a soft capsule base and Suspending agents of soft capsules; and the like.

In particular, in the case of the disintegrant, hydroxypropyl methyl cellulose, corn starch, agar powder methyl cellulose, bentonite hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose citrate, sodium lauryl sulfate anhydrous silicate, Dextran, ion exchange resin, polyvinyl acetate, formaldehyde treated casein, amylose guar gum, salted polyvinylpyrrolidone, calcium phosphate gelling starch, gum arabic, amylopectin, pectin sodium polyphosphate, ethylcellulose, One or more selected from the group consisting of sucrose, magnesium aluminum silicate, di-sorbitol solution, crospovidone, DST, croscarmellose sodium, and sodium starch glycolate, and in one embodiment, crospovidone, DST, cross This is done with sodium carmellose and sodium starch glycolate. It is preferable that it is 1 or more types chosen from the group which consisted of.

In order to increase the disintegration rate of the oral combination preparation of the present invention, the disintegrant may be used in excess. The excess means more than 20% by weight based on the total weight of the tablet including the statin drug.

In general, when an excessive disintegrant is used, the dissolution of the tablet may be accelerated. However, the oral combination formulation of the present invention may include a statin-based drug, although it may have an effect on the stability of the tablet by drawing moisture in the air. Since the purified tablet is incorporated into the capsule containing the omega-3 fatty acid ester, even when an excessive disintegrant is used, the tablet is completely blocked from moisture and thus does not affect the stability of the tablet.

In the oral combination formulation of the present invention, the envelope or envelope of the capsule containing the omega-3 fatty acid ester is arivaba gum, tracacanta gum, karaya gum, gati gum, guar gum, loggerhead bean gum, tara gum, konjac It may be composed of one or more components selected from the group consisting of gum, algin, agar, carrageenan, pullulan, pectin, gellan, mannan, glycerin, gelatin and xanthan gum. In one embodiment, the envelope may be concentrated glycerin or gelatin (eg, OMACOR ^® ).

The envelope of the capsules may be determined at the state of the art in terms of the type and content of ingredients so that the preparations such as omega-3 fatty acid esters contained therein can have an appropriate disintegration rate and dissolution rate.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited to these examples.

Example  One. Preparation of oral complex preparations of the present invention 1

<Manufacture of atorvastatin film coated tablets>

Using the composition shown in Table 1 below, atorvastatin calcium, microcrystalline cellulose, lactose monohydrate and calcium carbonate were mixed in a mixer, mixed with a binder solution (polysorbate 80, hydroxypropyl cellulose), and then a speed mixer granulator. After granulation at 8 ° C., dried at 50 ° C. for 8 hours, and then granulated using a power mill, and then mixed with croscarmellose sodium and magnesium stearate, and then compressed into tablet presses. Thereafter, a polyvinylacetate (PVA) and water were mixed to prepare a coating solution, and the tableted tablet was coated with the coating solution and then dried to prepare an atorvastatin film-coated tablet.

<Avastatin Film Coating Tablet Incorporation and Soft Capsule Forming>

Then, using a soft capsule film manufacturing machine to prepare a soft capsule shell using carrageenan and concentrated glycerin, the atorvastatin film-coated tablet is embedded therein, and after injecting omega-3 fatty acid ester, the soft capsule molding machine Sealed using.

Example 1
Contains statins Purification Department  (mg)
Atorvastatin calcium	21.7
Microcrystalline cellulose	40.0
Lactose Carb	54.5
Calcium carbonate	66.0
Croscarmellose Sodium	12.0
DST	-
Polysorbate 80	0.8
Hydroxypropyl cellulose	4.0
Magnesium stearate	1.0
refine Coating part  (mg)
HPMC	-
PVA	6
Capsule  Content solution (mg)
Omega-3	1,000
Capsule  Outer shell (mg)
Carrageenan	200
Concentrated glycerin	50

Example  2. Preparation of oral complex preparations of the present invention 2

In the tablet coating of Table 1 instead of polyvinylacetate A hydroxypropyl methyl cellulose (HPMC) was prepared in the same manner as in Example 1 except for 6 mg.

Example  3. Preparation of oral complex preparations of the present invention 3

Using the composition shown in Table 2 below, 7.5 mg of atorvastatin calcium, microcrystalline cellulose, lactose hydrate, calcium carbonate and croscarmellose sodium were mixed in a mixer, and mixed with a binder solution (polysorbate 80, hydroxypropyl cellulose). After granulating in a speed mixer granulator, the mixture was dried at 50 ° C. for 8 hours in a dryer, and then granulated using a power mill granulator, followed by post-mixing with 7.5 mg of croscarmellose sodium and magnesium stearate. It was compressed with the following rotary tableting machine. Thereafter, hydroxypropylmethylcellulose (HPMC) and water were mixed to prepare a coating solution, and the tableted tablets were coated with the coating solution and then dried to prepare an atorvastatin film-coated tablet. Then, the atorvastatin film-coated tablet incorporation and soft capsule molding process was prepared in the same manner as in Example 1.

Example 3
Contains statins Purification Department  (mg)
Atorvastatin calcium	21.7
Microcrystalline cellulose	40
Lactose Carb	51.5
Calcium carbonate	66
Croscarmellose Sodium	15
DST	-
Polysorbate 80	0.8
Hydroxypropyl cellulose	4
Magnesium stearate	One
refine Coating part  (mg)
HPMC	6
PVA	-
Capsule  Content solution (mg)
Omega-3	1,000
Capsule  Outer shell (mg)
Carrageenan	200
Concentrated glycerin	50

Example  4. Preparation of oral complex preparations of the present invention 4

It was prepared in the same manner as in Example 3 except that the amount of lactose monohydrate was reduced to 36.5 mg and the amount of croscarmellose sodium was increased to 30 mg in the statin purification unit of Table 2. The croscarmellose sodium was added in half and half to premix and postmix, respectively.

Example  5. Preparation of oral complex preparations of the present invention 5

In the mixing process of the atorvastatin and excipients was further prepared in the same manner as in Example 4 except that 15 mg of the disintegrant DST was further included and the lactose hydrate was reduced to 21.5 mg.

Example  6. Preparation of oral complex preparations of the present invention 6

<Manufacture of atorvastatin-coated tablets>

Using the composition shown in Table 3 below, atorvastatin calcium, calcium carbonate, pregelatinized starch and microcrystalline cellulose were mixed in a mixer, mixed with a binder solution (polysorbate 80, hydroxypropyl cellulose), and then a speed mixer was prepared. After granulating in granulator, it was dried for 8 hours at 50 ° C. in a dryer, and then granulated using a power mill granulator, and then mixed with sodium croscarmellose, sodium starch glycolate, magnesium stearate, and colloidal silicon oxide. The tablet was then compressed using a rotary tablet press. Thereafter, Opadry white (OY-C-7000A) and water were mixed to prepare a coating solution, the tablets were coated with the tableted liquid and then dried to prepare an atorvastatin tablet.

<Avavastatin-coated tablet penetration and capsule molding>

Next, after preparing a soft capsule shell using gelatin and concentrated glycerin by using a soft capsule film maker, the atorvastatin tablet was incorporated therein, and the omega-3-acid ethyl ester 90 was injected, followed by the soft capsule. Sealing was carried out using a molding machine.

Example  6
Contains statins Purification Department  (mg)
Atorvastatin calcium		10.85
Calcium carbonate		33.0
Croscarmellose sodium		8.0
Starch sodium glycolate		5.0
Pregelatinized starch		20.0
Microcrystalline cellulose		19.60
Polysorbate 80		0.4
Hydroxypropyl cellulose		2.0
Colloidal silicon dioxide		0.65
Magnesium stearate		0.50
refine Coating part  (mg)
HPMC		-
Opadray white (OY-C-7000A)		3.0
Capsule  Content solution (mg)
Omega-3-Acid Ethyl Ester 90		1,000
Capsule  Outer shell (mg)
gelatin	293.0
Concentrated glycerin	135.0

Example  7. Preparation of oral complex preparations of the present invention 7

<Manufacture of rosuvastatin coated tablets>

Using the composition shown in Table 4 below, rosuvastatin calcium and anhydrous calcium hydrogen phosphate were mixed in a mixer, mixed with microcrystalline cellulose, lactose monohydrate and crospovidone, and then magnesium stearate (extracted from Palm oil) was added and then mixed. After the process, I compressed it with a rotary tablet press. Thereafter, Opadry 03F640026 pink, ethanol and water were mixed to prepare a coating solution, and the tableted tablets were coated with the coating solution and then dried to prepare rosuvastatin tablets.

<Incorporation of rosuvastatin coated tablets and capsules>

Next, after preparing a soft capsule shell using gelatin and concentrated glycerin by using a soft capsule film maker, the rosuvastatin-coated tablet was incorporated into the inside, and the omega-3-acid ethyl ester 90 was injected. It was sealed using a capsule molding machine.

Example  7
Contains statins Purification Department  (mg)
Rosuvastatin Calcium		10.4
Lactose Carb		58.0
Microcrystalline cellulose		15.0
Anhydrous calcium hydrogen phosphate		10.9
Crospovidone		5.0
Magnesium stearate		1.5
refine Coating part  (mg)
Opadray 03F640026 pink		3.0
Capsule  Content solution (mg)
Omega-3-Acid Ethyl Ester 90		1,000
Capsule  Outer shell (mg)
gelatin	293.0
Concentrated glycerin	135.0

Comparative example  One. Atorvastatin  Preparation of Film-Coated Tablets

According to the prescription of the statin-based drug-containing tablet and tablet coating of Example 2, the atorvastatin film-coated tablet Prepared (without atorvastatin coated tablets and capsule formulation).

Comparative example  2. A statin-based drug is contained within a pharmaceutical formulation containing an omega-3 fatty acid ester. Najung  Preparation of Incorporated Complexes

Except that the film coating process in the above example was omitted (no tablet coating), it was prepared in the same manner as in Example 1 described in Table 1.

Comparative example  3. Atorvastatin  Commercial single tablet

A commercially available tablet (Lipitor; Pfizer Pharmaceuticals Co., Ltd.) mainly containing atorvastatin calcium was prepared as Comparative Example 3.

Comparative example  4. Preparation of a co-formulation containing a tablet containing a statin-based drug that does not contain a disintegrating agent in a pharmaceutical preparation containing an omega-3 fatty acid ester

It was prepared in the same manner as in Example 2 except that croscarmellose sodium was not included in the formulation and the lactose hydrate was increased to 66.5 mg.

Comparative example  5. Rosuvastatin  Preparation of Film-Coated Tablets

According to the prescription of the statin-based drug-containing tablet and tablet coating of Example 7, rosuvastatin coated tablets were prepared. (Rosvastatin coated tablet incorporation and capsule molding process omitted).

Experimental Example  One. Stability Test (Acceleration Test)

Samples prepared in Examples 1 and 2 and Comparative Examples 1 and 2 were stored at 40 ± 2 ° C. and 75 ± 5% RH, followed by Atoba for each sample after 0, 1, 2, 3 and 6 months. It is shown in Table 5 after calculating the content of the statin calcium. Comparative Examples 1 and 2 show a significant decrease in the content of atorvastatin calcium as the storage period exceeds 2 months, whereas Examples 1 and 2 show little change in the content even during the storage period of 6 months. That is, the composite formulations of Examples 1 and 2 showed excellent stability even in a long storage period.

Of atorvastatin calcium  content( % )
Month	Comparative Example 1	Comparative Example 2	Example 1	Example 2
0	100.72	101.02	100.98	100.82
One	100.81	99.42	101.12	100.62
2	99.98	97.96	100.61	101.21
3	99.25	95.42	100.12	100.42
6	97.03	90.23	99.25	99.72

Experimental Example  2. Stability test (long term test)

Samples prepared in Examples 1 and 2 and Comparative Examples 1 and 2 were stored at 25 ± 2 ° C. and 60 ± 5% relative humidity, and then after 0, 2, 4, 6, 8, 12 and 18 months After calculating the content of atorvastatin calcium for each sample is shown in Table 6 below. Comparative Examples 1 and 2 show a significant decrease in the content of atorvastatin calcium as the storage period exceeds 4 months, whereas Examples 1 and 2 show little change in the content even during the storage period of 6 months. That is, the composite formulations of Examples 1 and 2 showed excellent stability even in a long storage period.

Of atorvastatin calcium  content( % )
Month	Comparative Example 1	Comparative Example 2	Example 1	Example 2
0	100.52	100.92	100.23	100.45
2	100.14	97.56	100.42	100.74
4	100.34	95.21	100.27	100.42
6	99.46	91.12	100.16	100.34
8	99.14	88.13	99.98	100.26
12	97.25	80.42	99.46	99.56
18	96.75	72.48	99.14	99.37

Experimental Example  3. Stability test (long term test)

After storing the samples prepared in Example 3 and Comparative Example 3 at room temperature (20 ± 2 ℃) and 60 ± 5% relative humidity, the content of atorvastatin calcium for each sample after 0, 1 and 3 months It is shown in Table 7 after the calculation. The atorvastatin tablet contained in the soft capsule of Example 3 showed a similar degree of stability as compared to the atorvastatin single tablet of Comparative Example 3.

Of atorvastatin calcium  content( % )
Month	Comparative example  3	Example  3
0	103.7 ± 1.3	102.0 ± 0.9
One	100.6 ± 3.4	104.2 ± 0.9
3	102.4 ± 0.7	103.3 ± 0.4

Experimental Example  4. Stability test (long term test)

After storing the samples prepared in Example 3 and Comparative Example 3 at 45 ± 2 ℃ and 75 ± 5% RH, after calculating the content of atorvastatin calcium for each sample after 0, 1 and 3 months Table 8 shows. The atorvastatin tablet contained in the soft capsule of Example 3 showed a similar degree of stability as compared to the atorvastatin single tablet of Comparative Example 3.

Of atorvastatin calcium  content( % )
Month	Comparative example  3	Example  3
0	103.7 ± 1.3	102.0 ± 0.9
One	104.0 ± 1.4	102.6 ± 0.9
3	99.8 ± 1.0	99.7 ± 0.3

Experimental Example  5. Stability test (long term test)

After storing the samples prepared in Example 7 and Comparative Example 5 at room temperature (20 ± 2 ℃) and 60 ± 5% relative humidity, and after 0, 1 and 3 months, the content of rosuvastatin calcium for each sample After calculation, it is shown in Table 9 below. The rosuvastatin tablet contained in the soft capsule of Example 7 showed a similar degree of stability as compared to the rosuvastatin single tablet of Comparative Example 5.

Of rosuvastatin calcium  content( % )
Month	Comparative example  5	Example  7
0	100.2 ± 1.1	101.7 ± 1.4
One	99.8 ± 1.3	101.5 ± 1.3
3	99.5 ± 1.4	102.3 ± 1.2

Experimental Example  6. Stability test (long term test)

After storing the samples prepared in Example 7 and Comparative Example 5 at 45 ± 2 ℃ and 75 ± 5% RH, after calculating the content of rosuvastatin calcium for each sample after 0, 1 and 3 months Table 10 shows. The rosuvastatin tablet contained in the soft capsule of Example 7 showed a similar degree of stability as compared to the rosuvastatin single tablet of Comparative Example 5.

Of rosuvastatin calcium  content( % )
Month	Comparative example  5	Example  7
0	99.8 ± 0.9	102.1 ± 1.1
One	101.4 ± 1.2	100.8 ± 0.7
3	100.5 ± 1.1	101.2 ± 1.3

Experimental Example  7. Dissolution Test (1)

Atovastatin calcium according to the time of the samples prepared in Examples 3, 4 and 5 and Comparative Examples 3 and 4 under the following test conditions in accordance with the second method (Korean paddle method, KP) The dissolution rate of was measured. The results are shown in FIG.

Elution conditions: 1. Eluent: water

2. Eluent volume: 900 mL

RPM: 50 rpm

Experimental Example  8. Disintegration  exam

In order to determine the disintegration time of the composite preparations of Examples 1 and 7 and the tablets of Comparative Examples 1 and 5 prepared above, disintegration in an aqueous solution of pH 1.2 at 37 ° C. in accordance with the General Test Method Disintegration Test method of the Korean Pharmacopoeia The time was measured.

As a result, both the combination preparations of Examples 1 and 7 and the tablets of Comparative Examples 1 and 5 completely disintegrated in about 30 minutes. In other words, despite the inclusion of a statin-based drug-containing tablet inside the co-formulation, the capsules of the examples completely disintegrate in 30 minutes, and the omega-3 fatty acid esters flowed to the outside, and the disintegration degree was excellent. have.

Experimental Example  9. Dissolution Test (2)

Example 1 (atorvastatin calcium) and Example 7 (rosuvastatin calcium) according to the first method (rotational sample method) and the second method (general paddle method) of the Korean Pharmacopoeia Dissolution Test method The dissolution rate over time of the sample prepared in) was measured.

As a result, about 70-85% by weight of the statin-based drug was eluted based on the total weight of the combined formulations within 1 hour when the experiment was conducted under the conditions of 150 rpm according to the first method (rotational sample method). In addition, according to the second method (general paddle method), in the experiment at 100rpm condition, in Example 1 and Example 7, about 70 to 85% by weight of the statin-based drug was eluted based on the total weight of the combined preparation within 1 hour.

Claims (12)

1. Capsules containing omega-3 fatty acid esters; And oral complex preparations having a statin-based drug-containing tablets contained in the capsule.
2. The method of claim 1,

   The statin-based drugs are atorvastatin, rosuvastatin, rosuvastatin, lovastatin, simvastatin, pravastatin, fluvastatin and fluvastatin and pharmaceutically acceptable salts thereof. It is one or more selected from the group consisting of, oral complex preparations.
3. The method of claim 1,

   The statin-based drug-containing tablet further comprises a disintegrant, oral combination formulation.
4. The method of claim 3,

   The disintegrating agent is hydroxypropyl methyl cellulose, corn starch, agar powder methyl cellulose, bentonite hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose calcium citrate, sodium lauryl sulfate anhydrous silicic acid, dextran, ion Exchange resin, polyvinyl acetate, formaldehyde-treated casein, amylose guar gum, salted polyvinylpyrrolidone, calcium phosphate gelling starch, gum arabic, amylopectin, pectin sodium phosphate, ethylcellulose, white sugar, magnesium silicate Oral combination formulation, which is at least one selected from the group consisting of aluminum, di-sorbitol solution, crospovidone, DST, croscarmellose sodium and sodium starch glycolate.
5. The method of claim 3,

   The disintegrant is at least one selected from the group consisting of crospovidone, DST, croscarmellose sodium and sodium starch glycolate, oral combination preparation.
6. The method of claim 1,

   The omega-3 fatty acid ester is 30 to 80% by weight based on the total weight of the oral complex preparations, oral complex preparations.
7. The method of claim 1,

   The statin-based drug is 0.5 to 10% by weight based on the total weight of the oral combination formulation, oral combination formulation.
8. The method of claim 1,

   The statin-based drug-containing tablet is coated with a film coating base, oral combination formulation.
9. The method of claim 8,

   The film coating base is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and polyvinylacetate, oral complex preparations.
10. The method of claim 1,

    The outer shell of the capsule is arivaa gum, tracacanta gum, karaya gum, guati gum, guar gum, loggerhead bean gum, tara gum, konjac gum, algin, agar, carrageenan, flulan, pectin, gellan, mannan, glycerin, Oral combination formulation consisting of one or more components selected from the group consisting of gelatin and xanthan gum.
11. The method of claim 1,

    Statin-based drugs contained in the co-formulation is 70 to 85% by weight based on the total weight of the co-formulation in 30 minutes to 1 hour under the conditions according to the general paddle method, oral complex preparations.
12. The method of claim 1,

    Statin-based drugs contained in the combination formulation is 70 to 85% by weight based on the total weight of the combination formulation in 30 minutes to 1 hour under conditions according to the rotational test method, oral combination formulation.

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