KR20130003501A - Oral complex formulation comprising omega-3 fatty acid or ester thereof and hmg-coa reductase inhibitor - Google Patents

Abstract

PURPOSE: An oral complex formulation is provided to enhance HDL level in blood, to lower LDL and TG levels and to easily treat hyperlipidemia. CONSTITUTION: An oral complex formulation comprises: 100 parts by weight of a soft capsule core containing omega-3 fatty acid or ester thereof; 1-20 parts by weight of a first coating layer which contains a waterproof coating substrate and covers the core; and 5-20 parts by weight of a second coating layer which contains a HMG-CoA reductase inhibitor and sodium hydrogen carbonate and covers the first coating layer. The waterproof coating substrate is hydroxylethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymers, or ethyl cellulose. A pharmaceutical composition for preventing or treating hyperlipidemia contains the oral complex formulation. [Reference numerals] (AA) Rosuvastatin elution rate; (BB) Elution rate(%); (CC) Time(min); (DD) Crestor 100mg; (EE) Embodiment 3-2; (FF) Embodiment 4-1

Description

Oral complex formulation comprising omega-3 fatty acid or ester conjugate and HMG-CoA reductase inhibitor}

The present invention relates to an oral complex preparation containing a high release rate HMG-CoA reductase inhibitor that does not exhibit a delayed release even after long-term storage and has excellent stability of an omega-3 fatty acid or an ester thereof and an HMG-CoA reductase inhibitor. .

Marine oils, commonly referred to as fish oils, are two omega-3 fatty acids known to modulate lipid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid. (docosahexaenoic acid) (DHA) is a good source. Omega-3 fatty acids lower serum triglycerides (TG), raise serum HDL-cholesterol, lower systolic and diastolic blood pressure and pulse rate, and lower the activity of the blood coagulation factor phospholipid complex. In addition, to date, omega-3 fatty acids are considered to be well tolerated without causing any side effects. The omega-3 fatty acids currently sold as prescription drugs are omega-3 fatty acid ethyl esters (hereinafter referred to as omega-3 fatty acid esters) to etch omega-3 fatty acids, polyunsaturated fatty acids from fish oils containing DHA and EPA. Esterified concentrate, marketed under the OMACOR brand. Omega-3 fatty acid esters of this type are described in US Pat. Nos. 5,502,077, 5,656,667 and 5,698,594, which are in the form of soft capsules made of gelatin.

It is well known that high blood cholesterol is a major risk factor for coronary heart disease (CHD). Prior to 1987, lipid lowering therapeutic tools were substantially limited to low saturated fat and cholesterol meals, bile acid inhibitors (cholestyramine and cholestipol), nicotinic acid (niacin), fibrate, and probucol. Later, with the introduction of lovastatin (MEVACOR; see US Pat. No. 4,231,938), the first inhibitor of an HMG-CoA reductase inhibitor was made available in a prescription in 1987, for the first time doctors used plasma cholesterol with little side effects. It could be reduced relatively large.

In addition to natural fermentation products, mevastatin and lovastatin, currently simvastatin (ZOCOR; see US Pat. No. 4,444,784), pravastatin sodium salt (PRAVACHOL; see US Pat. No. 4,346,227), fluvastatin sodium salt (LESCOL; US Pat. No. 5,354,772), atorvastatin calcium salt (LIPITOR; US Pat. No. 5,273,995), cerivastatin sodium salt (rivastatin; see US Pat. No. 5,177,080), roschvastatin calcium salt (CRESTOR; Korean Patent No. 10-0105431) and pitavastatin calcium salts (Livaro; Korean Patent No. 10-0101149), including various semisynthetic and fully synthetic HMG-CoA reductase inhibitors. The HMG-CoA reductase inhibitors described above belong to the structural class of compounds comprising moieties that may exist as 3-hydroxy lactone rings or the corresponding ring-opened dihydroxy openacids, often referred to as "statins". Lose. Typically statin monotherapy has been used to maintain cholesterol levels at normal levels. Statins reduce cholesterol by inhibiting the enzyme HMG-CoA reductase, which regulates the body's cholesterol production rate, by slowing the production of cholesterol or increasing the liver's ability to remove LDL cholesterol already in the blood. Therefore, the main effect of the statin is to lower the LDL cholesterol. Statins are known to reduce CHD risk by about one third. However, statins have limited effects on TG and HDL.

Most of these HMG-CoA reductase inhibitors are designed to be released quickly in the gastrointestinal tract. In addition, HMG-CoA reductase inhibitors are rapidly absorbed in the upper intestine, and commercially available products also have a T _max of 4 hours for simvastatin, 1 to 2 hours for atorvastatin, less than 1 hour for pitavastatin, and 3 to 5 hours for roschvastatin. It's fast enough.

Particularly, when commercial products such as rochevastatin and pitavastatin among amorphous HMG-CoA reductase inhibitors use amorphous raw materials, hydrolysis of the main components is good and lactone-type flexible substances are generated as hydrolysis products, so roschvastatin Cresto, a commercially available product, contains a stabilizing composition.

Patients with hypercholesterolemia and complex dyslipidemia have both elevated LDL and TG levels. Combination administration of omega-3 fatty acid esters and statins has the advantage of being applicable to such high LDL and triglyceride levels. In addition, there are many statin formulations, but there is a continuing need for commercially available statin pharmaceutical compositions that include components that exhibit improved bioavailability, are easily formulated and administered and enhance the anticholesterolemic effect of statins. Therefore, when omega-3 fatty acid esters and statins are developed as a combination, it is advantageous to be efficiently formulated because it can raise blood HDL levels and lower LDL and TG levels as a hyperlipidemic agent.

As the combination prescription of the two drugs has an advantage, a combination formulation such as omega-3 fatty acid ester has been studied in various ways.

However, when the omega-3 fatty acid ester and the statin-based drugs are directly mixed, there is a problem in that the stability between the two drugs cannot be completely guaranteed.

Accordingly, the present inventors have a release rate equivalent to that of a commercial product of the HMG-CoA reductase inhibitor, do not show a release delay even after long-term (accelerated) storage, and include an excellent stability omega-3 fatty acid ester and HMG-CoA reductase inhibitor As a result of intensive studies to develop a complex formulation, a membrane layer comprising a waterproof coating substrate is coated on a soft capsule core containing an omega-3 fatty acid ester, and then a drug layer including a specific coating substrate and an HMG-CoA reductase inhibitor. By coating, the HMG-CoA reductase inhibitor not only has a fast release rate, but also shows no release delay even after accelerated and severe storage, and it is possible to prepare a complex formulation of a stable omega-3 fatty acid ester and an HMG-CoA reductase inhibitor. Confirmed that the present invention was completed.

The present invention does not exhibit a delayed release even after long-term storage, and as an agent for treating hyperlipidemia, it is possible to easily increase the level of HDL and lower LDL and TG levels in the blood, and thus to reduce omega-3 fatty acids or esters thereof and HMG-CoA for treating hyperlipidemia. Provided is an oral combination formulation comprising an enzyme inhibitor.

The present invention also provides a method for preparing the oral complex formulation.

In addition, the present invention provides a pharmaceutical composition for preventing or treating hyperlipidemia, including the oral complex preparation.

In order to solve the above problems, the present invention is a soft capsule core containing an omega-3 fatty acid or an ester thereof; A first coating layer comprising a waterproof coating substrate and surrounding the core; And a HMG-CoA reductase inhibitor and sodium hydrogen carbonate, the second coating layer surrounding the first coating layer.

As used herein, the term 'omega-3 fatty acid' means a natural or synthetic omega-3 fatty acid, and pharmaceutically acceptable esters, derivatives, precursors or salts thereof and mixtures thereof. Examples of omega-3 fatty acids include eicosapenta-5,8,11,14,17-econic acid (hereinafter 'EPA'), docosahexa-4,7,10,13,16,19-econic acid (hereafter 'DHA') and omega-3 polyunsaturated long chain fatty acids such as α-linolenic acid; Esters of glycerol and omega-3 fatty acids, such as mono-, di-, and triglycerides; Esters of primary alcohols with omega-3 fatty acids such as fatty acid methyl esters and fatty acid ethyl esters; Precursors of omega-3 fatty acid oils such as EPA and DHA precursor α-linolinic acid; And derivatives such as polysaccharide derivatives or polyoxyethylene derivatives. Preferably the omega-3 fatty acids are EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof. Omega-3 fatty acids or their esters, derivatives, precursors, salts and mixtures thereof can be used in pure form or as components of fish oils, preferably highly refined fish oil concentrates, perilla oils, or marine microalgal oils. Can be.

The omega-3 fatty acids or esters thereof of the present invention have the form of soft capsules and constitute the core of the oral complex preparations of the present invention.

The term 'first coating layer' used in the present invention means a layer coated on the surface of the core. The combination of omega-3 fatty acids and HMG-CoA reductase inhibitors has the advantage of effective treatment, but various components, including water, of omega-3 fatty acids affect HMG-CoA reductase inhibitors, resulting in large amounts of flexible substances. There was a problem that there was a lot of restrictions on the actual use. However, in the present invention, since the first coating layer includes a waterproof substrate, it is possible to prevent various components including moisture of the soft capsule, which is the core, from affecting the HMG-CoA reductase inhibitor included in the second coating layer. There is a characteristic.

The waterproof coating substrate is at least one selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer and ethyl cellulose desirable. More preferably ethyl cellulose can be used. According to one embodiment of the present invention, it was confirmed that the flexible material is significantly lower than the case in which ethyl cellulose is not included in the waterproof coating substrate.

It is preferable that the said 1st coating layer contains 1-20 weight part with respect to 100 weight part of said cores. If less than 1 part by weight, the endothelial coating layer is too thin to affect the separation and water transfer between the two drugs, thereby significantly reducing the effect of suppressing the generation of the flexible material. Moreover, when it exceeds 20 weight part, since the thickness of a 1st coating layer becomes too thick, the combined administration effect of omega-3 fatty acid and a HMG-CoA reductase inhibitor will become remarkably low.

The term 'second coating layer' used in the present invention means a layer coated on the surface of the first coating layer. The second coating layer includes HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitor. The HMG-CoA reductase inhibitor refers to a drug used for hyperlipidemia, hypercholesterolemia and atherosclerosis because it prevents HMG-CoA from being reduced to mevalonate, thereby lowering blood lipid concentration and cholesterol. . In the present invention, any one or a pharmaceutically acceptable salt thereof selected from the group consisting of simvastatin, pravastatin, fluvastatin, atorvastatin, cervastatin, roschvastatin and pitavastatin may be used as the HMG-CoA reductase inhibitor. Can be. Preferably roschvastatin can be used. It is preferable to include 0.5 to 2 parts by weight of the HMG-CoA reductase inhibitor with respect to 100 parts by weight of the core.

The second coating layer substrate is a substrate coated with a HMG-CoA reductase inhibitor, from the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol and polyvinylpyrrolidone-polyethylene glycol graft polymer Any one or more selected may be used. The second coating layer substrate contributes to the rapid release of the HMG-CoA reductase inhibitor, and serves to prevent the release of the HMG-CoA reductase inhibitor is delayed during storage.

In addition, the second coating layer comprises sodium hydrogen carbonate. The HMG-CoA reductase inhibitor has a disadvantage in that hydrolysis occurs well due to the chemical structure, and the weakness of the drug decreases due to the occurrence of a flexible substance having a lactone structure as a product of hydrolysis. Therefore, in the present invention, by including sodium hydrogen carbonate, the hydrolysis of the HMG-CoA reductase inhibitor can be suppressed to suppress the formation of a flexible substance. Since the oral complex preparation of the present invention contains the HMG-CoA reductase inhibitor and omega-3 fatty acid together, it is possible to inhibit the hydrolysis of the HMG-CoA reductase inhibitor to inhibit the formation of the flexible substance. The choice is important. According to one embodiment of the present invention, it was confirmed that other materials similar to sodium bicarbonate (eg, CaCO ₃ ) could not effectively suppress the formation of the flexible material.

It is preferable that 1 to 15 parts by weight of the sodium bicarbonate is included with respect to 100 parts by weight of the second coating layer. When the content of sodium hydrogen carbonate is less than 1 part by weight, the effect of suppressing the formation of the flexible substance is significantly lowered. In addition, when the content of sodium bicarbonate is more than 15 parts by weight, there is a problem that the production of the flexible material rather increases. More preferably, the sodium hydrogen carbonate is included in an amount of 4 to 7.5 parts by weight based on 100 parts by weight of the core. According to one embodiment of the present invention, it was confirmed that when the sodium bicarbonate was included in an amount of 4 to 7.5 parts by weight, generation of the flexible material was significantly suppressed compared to other contents.

It is preferable that the said 2nd coating layer contains 5-20 weight part with respect to 100 weight part of said cores. If the content is less than 5 parts by weight, the content of the HMG-CoA reductase inhibitor is too low, so the effect of coadministration of the omega-3 fatty acid and the HMG-CoA reductase inhibitor is significantly lowered. In addition, when more than 20 parts by weight, the content of the HMG-CoA reductase inhibitor is increased to produce a lot of analogues. More preferably, the second coating layer preferably contains 10 to 15 parts by weight based on 100 parts by weight of the core.

In addition, the oral complex preparation may further include a pharmaceutically acceptable additive, and an appropriate amount of a commonly used disintegrant, diluent, stabilizer, binder and glidant may be used.

The oral complex preparations according to the invention can be prepared in the form of coated tablets according to conventional formulation methods. For example, preparing a soft capsule core containing an omega-3 fatty acid or an ester thereof; Coating the core with a coating solution made by dissolving a waterproof substrate in a solvent suitable for coating (eg, a mixed solvent of ethanol and water), and then drying the core to form a first coating layer; At least one selected from the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethyleneglycol and polyvinylalcohol-polyethyleneglycol graft polymer, a HMG-CoA reductase inhibitor and sodium hydrogencarbonate , A mixed solvent of ethanol and water) provides a composite oral formulation according to the present invention comprising the step of coating the core formed with the first coating layer with a coating solution and drying to form a second coating layer.

In addition, the present invention provides a pharmaceutical composition for preventing or treating hyperlipidemia, including the oral complex preparation.

The oral combination preparation according to the present invention releases at least 80% of the HMG-CoA reductase inhibitor within 30 minutes of release test (0.05M citrate buffer) and even after 6 months storage at 40 ° C., 75% relative humidity (RH) conditions. Since it does not show a delay phenomenon, it can be usefully used as a complex preparation for treating hyperlipidemia because it can raise HDL levels in blood and lower LDL and TG levels.

1 shows a linear graph of water absorption of the formulations of Examples 1-1 to 1-3.
Figure 2 shows the dissolution rate graph of Cresto, a control agent of Rochevastatin, and the formulations of Examples 1-1, 2-4, and 3-2.
Figure 3 shows the dissolution rate graph of Cresto, a control agent of Rochevastatin, and Examples 2-1 to 2-4.
Figure 4 shows the initial dissolution rate and the dissolution rate of the accelerated 1, 3, 6 months of Cresto, a control agent of Rochevastatin, and Example 2-1.
5 shows a graph of initial dissolution rate and dissolution rate of accelerated 1, 3, and 6 months of Cresto, a control agent of Rochevastatin, and Example 2-4.
Figure 6 shows a graph of the initial dissolution rate and the dissolution rate of accelerated 1, 3, 6 months of Cresto, a control agent of Rochevastatin, and Example 3-1.
FIG. 7 shows graphs of initial dissolution rates and dissolution rates of accelerated 1, 3 and 6 months of Cresto, a control agent of Rochevastatin, and Example 3-2.
8 shows a graph of initial dissolution rate and dissolution rate of accelerated 1, 3 and 6 months of Cresto, a control agent of Rochevastatin.
Figure 9 is a graph showing the change in the initial and accelerated content of 1, 3, 6 months of Cresto, a control agent of Rochevastatin, and Examples 2-1, 2-4, 3-1, and 3-2.
FIG. 10 is a graph showing changes in individual analogs of the initial and accelerated 1, 3 and 6 months of Example 2-1 formulation. FIG.
11 is a graph showing changes in the individual analogs of the initial and accelerated 1, 3 and 6 months of the formulation of Example 2-4.
12 is a graph showing changes in the individual analogs of the initial and accelerated 1, 3 and 6 months of the formulation of Example 3-1.
FIG. 13 is a graph showing changes in individual analogs of the initial and accelerated 1, 3 and 6 months of Example 3-2 formulation. FIG.
FIG. 14 is a graph showing changes in individual analogues at initial and accelerated periods of 1, 3, and 6 months of cresto, a control agent of roschvastatin.
FIG. 15 is a graph showing changes in total analogues of initial and accelerated 1, 3 and 6 months of Cresto and Rosvastatin as control agents and Examples 2-1, 2-4, 3-1 and 3-2 formulations. to be.
FIG. 16 is a graph showing changes in the soft substances of 3R and 5S Lactone at the initial and accelerated stages 1, 3, 6, and months of Example 4-1 and Comparative Example 1 formulations in the Rochevastatin coating layer.
FIG. 17 is a graph showing changes in the soft substances of 3R and 5S Lactone at initial and accelerated stages 1, 3, 6, and months according to the amount of sodium bicarbonate added to the Rochevastatin coating layer.
Fig. 18 is a graph showing initial dissolution rates of Cresto as a control agent of Rochevastatin and Examples 3-2 and 4-1.

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 by these examples.

Example 1: Measurement of disintegration time and moisture absorption rate according to the first coating layer

In order to measure the disintegration time and water absorption rate according to the first coating layer of the oral complex preparation, it was carried out as follows.

1) Preparation of Examples 1-1 to 1-3

A mixture of 1,000 mg equivalent of omega-3 fatty acid ester oil and 10 mg of roschvastatin was uniformly mixed to prepare a mixture (Example 1-1).

In addition, according to the composition shown in Table 1, hydroxypropyl methyl cellulose, polyethylene glycol, polyvinyl birrolidone, ethyl cellulose is mixed with a solvent consisting of alcohol and water and then coated using a general coating machine (SEJONG, SFC-30) A soft capsule including (Example 1-2) and a coating (Example 1-3) showing waterproof properties were prepared.

mg / Capsule Examples 1-2 Example 1-3 HPMC 2910 (P645) 74.0 74.0 PEG6000 10.0 10.0 PVP K-30 10.0 10.0 Ethyl Cellulose - 26.5 (Ethanol) (1036.0) (1036.0) (DW) (444.0) (444.0) Total weight of coating base 94.0 120.5

2) Measurement of disintegration time according to the type of the first coating layer

The formulations prepared in Examples 1-1 (the first coating layer member), Examples 1-2 (the first coating layer is a general coating) and Examples 1-3 (the first coating layer has waterproof properties) Disintegration test was carried out according to the disintegration test method, the results are shown in Table 2 below.

Example Disintegration time Example 1-1 7 minutes 30 seconds Examples 1-2 10 minutes 50 seconds Example 1-3 13 minutes 00 seconds

As shown in Table 2, it can be confirmed that the disintegration in the order of Example 1-1, Example 1-2, Example 1-3, the first coating layer containing a waterproof base material from the results You can see it blocking.

3) Measurement of water absorption according to the type of the first coating layer

After drying the formulations prepared in Example 1-1, Example 1-2, and Example 1-3 with excessive humidity (20 ° C., 45% RH) for a long time (1 month), the type of the first coating layer The degree of absorbing moisture was measured by calculating the weight change ratio to the initial mass, and the results are shown in FIG. 1.

As shown in FIG. 1, it can be seen that Example 1-3 has a significantly lower mass growth rate than Examples 1-1 and 1-2, and the first coating layer including the waterproof substrate exhibits water absorption. You can see it blocking.

Example 2: Dissolution rate measurement according to the second coating layer

In order to measure the dissolution rate according to the second coating layer of the oral complex preparation, it was carried out as follows.

1) Preparation of Examples 2-1 to 2-4

Using the soft capsule as a core of the formulation prepared in Example 1-2, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol- with roschvastatin according to the composition shown in Table 3 below. The polyethyleneglycol graft polymer or a mixture thereof was dissolved in a mixture of ethanol and water, coated, and dried to form a second coating layer.

mg / Capsule Example 2-1 Example 2-2 Example 2-3 Examples 2-4 Rosuvastatin ca 10.4 10.4 10.4 10.4 HPMC 2910 (P645) 46.0 26.1 10.4 - PEG6000 6.2 6.2 6.2 - Kollicoat IR - - - 52.2 PVP K-30 6.2 26.1 41.8 6.2 (Ethanol) 644.0 644.0 644.0 460.0 (DW) 276.0 276.0 276.0 460.0 Total weight of coating base 68.8 68.8 68.8 68.8

In Examples 2-1 to 2-4, the ratio of hydroxypropyl methylcellulose and polyvinylpyrrolidone was about 9: 1 (Example 2-1), 5: 5 (Example 2-2), 2 Each was adjusted to: 8 (Example 2-3), and Example 2-4 used a polyvinyl alcohol-polyethylene glycol graft polymer instead of hydroxypropyl methylcellulose and polyvinylpyrrolidone. At this time, the temperature at the time of coating was adjusted to 45 ℃, the product temperature was 30 ℃, and dried after 30 minutes to remove the ethanol and water remaining after the coating.

2) Dissolution test according to the type of second coating layer

Using the formulations of Examples 2-1 to 2-4, the dissolution test was carried out in a dissolution test solution of 0.05 mL citrate buffer solution at a rotational speed of 50 rpm paddle method, the second method of the Korean pharmaceutical dissolution. In addition, cresto which is an original formulation of roschvastatin was used as a comparative formulation. 5, 10, 15, 30, 45 minutes after the start of dissolution, the eluate was taken to calculate the dissolution rate of Rochevastatin, and the dissolution rate graph is shown in FIG. 3.

As shown in Figure 3, through the results of Examples 2-1 to 2-3, the higher the ratio of polyvinylpyrrolidone in the ratio of hydroxypropyl methylcellulose and polyvinylpyrrolidone increases the dissolution rate. I could confirm it. In addition, in the case of Example 2-4 using a polyvinyl alcohol-polyethylene glycol graft polymer in place of hydroxypropyl methylcellulose and polyvinylpyrrolidone, Roschvastatin compared to Examples 2-1 to 2-3 It was confirmed that the resultant elution was closer to Crestor, the original preparation of.

Based on the above results, the experiment was continued with the same formulation as in Example 2-4 including the polyvinyl alcohol-polyethylene glycol graft polymer.

Example 3 Measurement of Dissolution Rate, Roschvastatin Content and Softening Material According to Combination of First and Second Coating Layers

In order to measure the dissolution rate and the content change of Rochevastatin according to the combination of the first coating layer and the second coating layer of the oral complex preparation, it was carried out as follows.

1) Preparation of Examples 3-1 and 3-2

On the same first coating layer as the formulation prepared in Example 1-3, the same second coating layer as Example 2-1 (Example 3-1) and same second coating layer as Example 2-4, respectively The coating was performed to prepare an oral complex formulation as shown in Table 4 below.

mg / Capsule Example 3-1 Example 3-2 First coating layer HPMC 2910 (P645) 74.0 74.0 PEG6000 10.0 10.0 PVP K-30 10.0 10.0 Ethyl Cellulose 26.5 26.5 Second coating layer Rosuvastatin ca 10.4 10.4 HPMC 2910 (P645) 46.0 - PEG6000 6.2 - Kollicoat IR - 52.2 PVP K-30 6.2 6.2

Specifically, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol-polyethylene glycol graft polymer or mixtures thereof with Rochevastatin are dissolved in a mixture of ethanol and water, coated, and then dried. The desired oral complex formulation was prepared by forming two coating layers. At this time, the temperature at the time of coating was adjusted to 45 ℃, the product temperature was 30 ℃, and dried after 30 minutes to remove the ethanol and water remaining after the coating.

2) Dissolution rate measurement according to the combination of the first coating layer and the second coating layer

Using the formulation of Example 1-1 without the first coating layer and the second coating layer, the formulation of Example 2-4 in which the first coating layer is not a waterproof substrate, and the formulation of Example 3-2 prepared above, The dissolution rate was measured as well. In a dissolution test solution of 900 mL of 0.05 M citrate buffer solution, the dissolution test was performed at a rotational speed of 50 rpm of the paddle method, the second method of the Korean pharmaceutical dissolution. In addition, cresto which is an original formulation of roschvastatin was used as a comparative formulation. 5, 10, 15, 30, 45 minutes after the start of dissolution, the eluate was taken to calculate the dissolution rate of Rochevastatin, and the dissolution rate graph is shown in FIG. 2.

As shown in Figure 2, the formulation of Example 1-1 was confirmed that the dissolution rate of Rochevastatin is significantly lower than the formulation of Examples 2-4 and Example 3-2. In addition, in the case of the formulations of Examples 2-4 and 3-2, almost the same dissolution rate was confirmed. From the above results, the type of the first coating layer itself is not involved in the dissolution rate of the initial stage roschvastatin, and the simple mixture is eluted in comparison with the roschvastatin control (cresto) and the formulation with the first coating layer and the second coating layer. You can see that it is slow.

3) Dissolution rate measurement during accelerated storage period according to the combination of the first coating layer and the second coating layer

The formulations of Examples 2-1, 2-4 and Examples 3-1 and 3-2 were packaged in HDPE bottles and stored under 40 ° C. and 75% relative humidity conditions (acceleration conditions). Samples were taken after 1, 3, and 6 months under accelerated conditions from the start of the test, and the dissolution rate of Rochevastatin was confirmed by the same method as the above test, and the results are shown in FIGS. 4 to 8.

As shown in Figures 4 to 8, it can be seen that the formulations of Examples 2-1 and 2-4 all showed a significant dissolution decrease phenomenon under accelerated conditions. On the other hand, it can be seen that the formulations of Examples 3-1 and 3-2 having the first coating layer of the waterproof substrate are stable with almost no dissolution lowering phenomenon.

In addition, the formulation of Example 3-2, which was subjected to Roschvastatin drug coating including a polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat IR) after coating the first coating layer on the waterproof substrate, and hydroxypropyl methyl cellulose (HPMC 2910 ( In the case of Example 3-1 based on P645)), compared with the formulations of Examples 2-1 and 2-4, respectively, the rate of decrease in the dissolution rate was small when based on hydroxypropyl methylcellulose. However, the formulation showing a dissolution rate similar to that of the control (cresto) was the formulation of Example 3-2.

4) Measurement of the content change of Rochevastatin according to the combination of the first coating layer and the second coating layer

The formulations of Examples 2-1, 2-4, 3-1, and 3-2 were packaged in HDPE bottles and stored under 40 ° C. and 75% relative humidity conditions (acceleration conditions). After the start of the test, the samples were taken after 1, 3 and 6 months, and the contents of Rochevastatin were confirmed by referring to the standards and test methods of Rochevastatin's own product (Subust), and the results are shown in Table 5 (unit:%). (w / w)) and FIG. 9.

Cresto 10mg Example 2-1 Examples 2-4 Example 3-1 Example 3-2 Initial 101.0 ± 0.5 100.0 ± 0.9 100.0 ± 1.3 100.0 ± 2.1 100.0 ± 1.1 1 month acceleration 102.7 ± 1.0 92.4 ± 5.0 89.0 ± 4.2 98.7 ± 3.7 100.6 ± 3.3 3 months acceleration 103.8 ± 2.7 82.6 ± 8.2 78.3 ± 1.1 96.4 ± 1.6 98.9 ± 1.4 Accelerated 6 months 100.5 ± 0.1 78.6 ± 7.5 60.4 ± 5.7 95.2 ± 4.2 98.7 ± 4.6

As shown in Table 5 and FIG. 9, the formulations of Examples 2-1 and 2-4 were all decreased in proportion to the storage period, whereas Examples 3-1 and 3-2 both exhibited a content reduction phenomenon. It can be seen that it is relatively stable with little indication. This indicates that the first coating layer of the waterproof substrate between the omega-3 fatty acid ester soft capsule and the rochevastatin drug coating effectively has an effective effect of blocking conditions such as moisture which may affect stability.

5) Measurement of Flexible Material Changes of Rochevastatin According to Combination of First and Second Coating Layers

The formulations of Examples 2-1, 2-4, 3-1 and 3-2 were packaged in HDPE bottles and stored under 40 ° C. and 75% relative humidity conditions (acceleration conditions). Samples were taken 1, 3, and 6 months after the start of the test, and the flexible substances of Rochevastatin were identified by referring to the standards and test methods of Rochevastatin's own product (Subust). The results are shown in Tables 6 to 8 (unit:% (w / w)), and FIGS. 10 to 15.

Leading substance name RRT Example 2-1 Examples 2-4 Early Acceleration
1 month Acceleration
3 months Acceleration
6 months Early Acceleration
1 month Acceleration
3 months Acceleration
6 months unk1 0.67 - - - 0.37 - 0.35 1.88 4.08 unk2 0.72 0.12 1.58 2.46 3.02 0.15 4.33 8.90 10.79 B1 0.84 0.30 0.31 0.23 0.34 0.33 0.39 0.16 0.22 B2 1.58 0.12 0.25 0.47 0.60 0.24 0.35 0.58 0.70 3R, 5S lactone 2.22 0.44 2.10 2.82 4.06 0.38 4.90 9.04 11.56 Total Flexible Material 0.98 4.24 5.98 8.39 1.10 10.32 20.55 27.35

Leading substance name RRT Example 3-1 Example 3-2 Early Acceleration
1 month Acceleration
3 months Acceleration
6 months Early Acceleration
1 month Acceleration
3 months Acceleration
6 months unk1 0.67 0.45 0.54 0.88 1.12 - - - - unk2 0.72 - 0.68 0.99 1.47 - 0.08 0.13 0.21 B1 0.84 0.31 0.39 0.25 0.42 0.09 0.09 0.09 0.09 B2 1.58 0.05 0.07 0.10 0.20 0.04 0.05 0.08 0.10 3R, 5S lactone 2.22 0.17 0.80 1.30 1.96 0.08 0.26 0.31 0.41 Total Flexible Material 1.48 2.49 3.53 5.17 0.21 0.48 0.61 0.81

Leading substance name RRT Cresto 10mg Early 1 month acceleration 3 months acceleration Accelerated 6 months B1 0.84 0.09 0.15 0.14 0.14 B2 1.58 0.14 0.22 0.25 0.27 3R, 5S lactone 2.22 - 0.12 0.46 0.46 Total Flexible Material 0.23 0.48 0.85 0.88

From Tables 6 to 8 and Figures 10 to 15, the formulations of Examples 2-1 and 2-4 all increase in the flexible material in proportion to the storage period under accelerated storage conditions, whereas Examples 3-1 and 3-2 It can be seen that it is relatively stable. The results indicate that the barrier coating between the omega-3 fatty acid ester soft capsule and the rochevastatin drug coating has an effective effect of effectively blocking conditions such as moisture, which may affect stability. In particular, in the case of Example 3-2, compared to the control agent (Cresto), it can be confirmed that the flexible material is generated lower than the control agent is more stable.

Based on the above experimental results, it could be confirmed that Example 3-2 having almost no change in content and flexible substance and the dissolution rate similar to that of Rochevastatin tablet was the most stable and effective formulation.

Example 4 Determination of Lead and Dissolution Rate of Sodium Hydrogen Carbonate

In order to measure the change in the elution rate and the lead material according to the sodium bicarbonate added to the second coating layer was carried out as follows.

1) Preparation of Examples 4-1 to 4-4

To prepare the same formulation as in Example 3-2, to prepare a formulation of Examples 4-1 to 4-4 by adding sodium hydrogen carbonate to the second coating layer as shown in Table 9. In addition, Comparative Example 1 formulations were prepared using CaCO ₃ instead of sodium bicarbonate.

Example 4-1 Example 4-2 Example 4-3 Example 4-4 Comparative Example 1 NaHCO ₃ 10 mg 5 mg 3 mg 1 mg - CaCO ₃ - - - - 10 mg

2) Determination of changes in analogues of rochevastatin during severe and accelerated storage

The most stable case is the case of the waterproof barrier coating in Example 3-2 and the Rochevastatin drug coating including polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat IR). In this case, however, the flexible material increases over time under accelerated conditions. At this time, the basic stabilizer was mixed with the second coating layer and the coating was performed in the same manner as the above method.

The formulations of Examples 3-2, Examples 4-1 to 4-4 and Comparative Example 1 were packaged in HDPE bottles and stored under 40 ° C. and 75% relative humidity conditions (acceleration conditions). Samples were taken 1, 3, and 6 months after the start of the test, and the flexible substances of Rochevastatin were identified in the same manner by referring to the standards and test methods of Rochevastatin's own product (Subust). Unit:% (w / w)) and shown in FIGS. 16 and 17.

3R, 5S Lactone Lead Early 1 month acceleration 3 months acceleration Accelerated 6 months Example 4-1 - - - - Example 4-2 - - - 0.02 Example 4-3 0.05 0.06 0.08 0.15 Example 4-4 0.05 0.08 0.15 0.23 Comparative Example 1 0.05 0.07 0.10 0.17

As shown in Table 10, and FIGS. 16 and 17, the formulations of Examples 4-1 to 4-4 containing sodium bicarbonate had the highest effect as stabilizers. On the other hand, in the case of the formulation of Comparative Example 1, when compared with the same content of Example 4-1, it was confirmed that it does not effectively inhibit the production of 3R, 5S Lactone.

In addition, the formulations of Examples 2-1, 2-4, 3-1, and 3-2, which did not include sodium hydrogen carbonate, produced the soft substances unk 1 and 2, whereas Example 4 containing sodium hydrogen carbonate. In the case of the formulations of -1 to 4-4, the soft substances unk 1 and 2 were not produced. Therefore, it can be seen that sodium bicarbonate has a function as a stabilizer specific for roschvastatin.

3) Measurement of dissolution rate of complex preparation

Example 3-2 without sodium hydrogen carbonate and Example 4-1 with sodium hydrogen carbonate were dissolved in 900 mL of 0.05 M citrate buffer at a rotational speed of 50 rpm of the paddle method of the Korean Pharmacopoeia Elution. A dissolution test was conducted and the results are shown in FIG. 18.

As shown in FIG. 18, the dissolution rate of the formulation of Example 4-1 was slightly higher than that of Example 3-2, but showed a slight difference in initial dissolution rate. Elution of 80% or more within 30 minutes) was confirmed to be a suitable level.

Claims (11)

Soft capsule cores comprising omega-3 fatty acids or esters thereof;
A first coating layer comprising a waterproof coating substrate and surrounding the core; And
An oral composite formulation comprising a HMG-CoA reductase inhibitor and sodium hydrogen carbonate, the second coating layer surrounding the first coating layer.
The method of claim 1, wherein the waterproof coating substrate is from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer and ethyl cellulose Oral complex preparations, characterized in that any one or more selected.
The oral complex preparation according to claim 1, wherein the first coating layer comprises ethyl cellulose.
The method of claim 1, wherein the HMG-CoA reductase inhibitor is any one selected from the group consisting of simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, roschvastatin and pitavastatin, or a pharmaceutically acceptable compound thereof. Oral complex preparation, characterized in that the salt.
The method of claim 1, wherein the second coating layer comprises at least one selected from the group consisting of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol and polyvinylpyrrolidone-polyethylene glycol graft polymer Oral complex formulation, characterized in that.
According to claim 1, Oral complex preparations comprising 1 to 20 parts by weight of the first coating layer and 5 to 20 parts by weight of the second coating layer with respect to 100 parts by weight of the core.
According to claim 6, oral complex preparations comprising 10 to 15 parts by weight of the second coating layer.
The oral complex preparation according to claim 1, comprising 0.5 to 2 parts by weight of the HMG-CoA reductase inhibitor, based on 100 parts by weight of the core.
The oral complex preparation according to claim 1, comprising 1 to 15 parts by weight of the sodium hydrogen carbonate based on 100 parts by weight of the second coating layer.
The oral complex preparation according to claim 9, comprising 4 to 7.5 parts by weight of the sodium hydrogen carbonate based on 100 parts by weight of the second coating layer.
A pharmaceutical composition for the prevention or treatment of hyperlipidemia comprising the oral complex preparation of any one of claims 1 to 10.

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