KR20090028983A - New pharmaceutical composition for treatment of hypercholesterolemia - Google Patents

Abstract

A pharmaceutical composition for treating hypercholesterolemia is provided to maximize a treatment effect of hyperlipidemia by minimizing side effects caused by a HMG-CoA(3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor. A pharmaceutical composition for treating hypercholesterolemia comprises coenzyme Q 10, statin system drug, dissolution agent, surfactant, oil, antioxidant and pH adjusting agent. Nanoemulsion includes the coenzyme Q 10 and statin system drug in the same weight. The pH of nanoemulsion is controlled as 5.0-7.0 by comprising a pH adjusting agent of 0.1~5 weight% based on the whole weight of the nanoemulsion. The dissolution agent is polyethylene glycol, propylene glycol, triacetin, glycerol or diethylene glycol monoethyl ether. The oil is an oleic acid. The antioxidant is tocopherol, dibutyl hydroxytoluene, butyl-hydroxyanisol, ascorbic acid, sodium sulfite, sodium metabisulphite or sodium bisulfite. The pH adjusting agent is a citric acid, succinic acid, tartaric acid, formic acid or malic acid.

Description

New pharmaceutical composition for treatment of hypercholesterolemia

The present invention relates to a combination hyperlipidemia therapeutic agent for minimizing the side effects caused by the inhibition of the biosynthesis of coenzyme Q10 by the administration of a HMG-CoA (statin-based drug) reductase inhibitor widely used for the treatment of hyperlipidemia. The combination composition of statin-based hyperlipidemia, coenzyme Q10, maximizes the treatment effect of hyperlipidemia by controlling LDL (Low Density Lipoprotein), which is an effective low density lipoprotein, and reducing side effects from the reduction of coenzyme Q10 in the body.

In general, hyperlipidemia refers to an abnormally increased state of lipids such as cholesterol and triglycerides in plasma. Hyperlipidemia, especially hypercholesterolemia, leads to arterial thrombosis, which causes arteriosclerosis, in which lipids build up along the blood vessel walls. Therefore, hyperlipidemia and arteriosclerosis are closely related diseases. By treating hyperlipidemia, arteriosclerosis can be prevented. Drugs for hyperlipidemia are generally bile acid binding resins, fibric acid derivatives, HMG-CoA reductase inhibitors (weak with 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors) And nicotinic acid. Among these, statin-based drugs inhibit HMG-CoA, which converts acetyl CoA into mevalonic acid during cholesterol biosynthesis in the liver. As a result, cholesterol production decreases and the expression of low density lipoprotein particle receptors increases, leading to an increase in blood low density lipoprotein removal. In addition, the ultra low density lipoprotein concentration rich in triglycerides is also reduced. However, like the cholesterol biosynthesis pathway, coenzyme Q10 biosynthesis also has a pathway to convert acetylcoA to mevalonic acid, which not only reduces cholesterol production but also decreases the production of coenzyme Q10 required by the body. do. Therefore, the use of statin-based drugs is due to the reduction of coenzyme Q10 is not all of the role of coenzyme Q10 in the body, causing a number of side effects.

Coenzyme Q10 is called ubidecarenon, ubiquinone 10, and the like. It is a yellow-orange solid at room temperature, has no smell and taste, is soluble in ether, hardly soluble in water and anhydrous ethanol, is unstable in light, and has a melting point of about 48 ° C. Coenzyme Q10 is slowly absorbed upon oral administration and reaches a peak blood concentration of about 5 to 10 hours, and most of the dose administered enters the liver and is incorporated into very low-density lipoprotein (VLDL), followed by myocardial, It is distributed in various tissues such as lung, kidney, adrenal gland, and spleen, and the rate of excretion (half life) is about 34 hours, and it is known that it is mainly excreted in bile and is excreted through feces.

Coenzyme Q10 is a fat-soluble quinone that is involved in physiological processes at various cellular levels through metabolism. It is a coenzyme that plays an important role in mitochondrial electron transport system and ATP synthesis. Reduction of coenzyme Q10 is a result of the poor synthesis of ATP, which is used as an energy source in the body, thereby deteriorating biofunction. Coenzyme Q10 has excellent antioxidant activity, which mainly removes free radicals and prevents aging. In addition, a lack of coenzyme Q10 can lead to a lack of energy for the heart, leading to a decrease in the functioning of the heart, causing problems with blood circulation, and leading to various diseases such as leg swelling, hypotension and worsening of heart disease.

Therefore, in the present invention, in order to prevent various side effects due to the lack of coenzyme Q10 accompanying in the treatment of hyperlipidemia, a composition of a therapeutic agent for complex hyperlipidemia for oral administration consisting of a statin-based drug and coenzyme Q10 was completed.

The present invention simultaneously contains one drug and coenzyme Q10 (Coenzyme Q10) selected from a statin-based drug, namely simvastatin, Atovastatin Calcium, Rosuvastatin Calcium, in the treatment of hyperlipidemia. It relates to a new composition. The new composition can be used to treat hyperlipidemia effectively and to prevent side effects, thereby compensating for the disadvantages of statin-based drugs can be treated more safely hyperlipidemia.

According to a preferred embodiment of the present invention for solving the above problems, in the pharmaceutical composition containing a nanoemulsion containing coenzyme Q10, statin-based drugs, solubilizers, surfactants, oils, antioxidants and pH adjusters, the nanoemulsion is coenzyme Q10 and a statin-based drug are included in the same weight, and the pH adjuster is contained in an amount of 0.1 to 5% by weight based on the total weight of the nanoemulsion, thereby providing a pharmaceutical composition including the nanoemulsion in which the pH of the nanoemulsion is adjusted to 5.0 to 7.0. .

According to another suitable embodiment of the present invention, the solubilizing agent may be preferably used at least one selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, glycerol and diethylene glycol monoethyl ether.

According to another suitable embodiment of the present invention, the oils are preferably oleic acid.

According to another suitable embodiment of the present invention, the antioxidant is at least selected from the group consisting of tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, sodium sulfite, sodium pyrosulfite and sodium hydrogen sulfite 1 type can be used preferably.

According to another suitable embodiment of the present invention, the pH adjuster may be preferably used at least one selected from the group consisting of citric acid, succinic acid, tartaric acid, formic acid and malic acid.

According to another suitable embodiment of the present invention, the statin drug is preferably simvastatin, atorvastatin calcium or roschvastatin calcium.

The present invention provides a novel hyperlipidemic therapeutic composition containing coenzyme Q10 and a statin-based drug, and can greatly obtain two effects. First, solubilizing the statin drugs of simvastatin, atorvastatin calcium, and roschvastatin calcium, which are used as hyperlipidemia drugs, can improve absorption and increase bioavailability, and second, lack of coenzyme Q10 due to taking statin drugs Various side effects of solubilized coenzyme Q10 can be administered together to reduce side effects and maximize the therapeutic effect.

The coenzyme Q10 and statin-based drugs or pharmaceutically acceptable amounts thereof in the new pharmaceutical compositions of the present invention depend on several factors known to those skilled in the art, such as the extent of the patient's symptoms, the persistence of the desired use, and the like. The amount of coenzyme Q10 in the composition of the present invention is 1 to 20% by weight and the amount of statin-based drug is 1 to 20% by weight.

According to the present invention, pharmaceutical compositions of coenzyme Q10 and statin-based drugs can be prepared in encapsulated, tableted, emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to stabilize or enhance the composition or to facilitate the preparation of the composition. As the liquid carrier, syrup, soybean oil, olive oil, glycerin, propylene glycol, polyethylene glycol, ethanol and water can be suitably used. The carrier may also comprise a series of release materials, such as glyceryl monostearate and glyceryl distearate, alone or in combination with waxes. The amount of solid carrier may vary but preferably from about 20 mg to about 1 g per dosage unit. Pharmaceutical preparation is carried out according to conventional preparations including grinding, mixing, granulating and, if necessary, compression processes for tablets, and grinding, mixing and filling for light gelatine capsules. If a liquid carrier is used, it can be prepared in the form of syrups, elixirs, emulsions or aqueous or non-aqueous suspensions. Such formulations may be administered either directly or filled in soft gelatin capsules.

Coenzyme Q10 may be solubilized in order to speed up the effect of coenzyme Q10 in preparing soft capsules containing the pharmaceutical composition of the present invention. The composition of the nanoemulsion as a soft capsule solution for solubilization is as follows. 1-20% by weight of coenzyme Q10 relative to the total weight; 1-20% by weight of statin-based drug; Solubilizer corresponding to 10 to 70% by weight; Surfactant corresponding to 10 to 70% by weight; Oils corresponding to 1 to 20% by weight; Antioxidants corresponding to 0.1 to 20% by weight; It provides a soft capsule composition comprising coenzyme Q10 and a statin-based drug-containing nanoemulsion comprising a pH adjuster corresponding to 0.1 to 5% by weight.

Specifically, coenzyme Q10 and statin-based drugs which are poorly soluble in water may be dissolved in polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, glycerol, triacetin and the like; Surfactants such as polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbates, polyethylene glycol-8 glyceryl caprylate, dimethyl isosorbide and poloxamer; Oil components such as fatty acids, monohydric alkanols and ester compounds, intermediate fatty acid triglycerides and fatty acid monoglycerides for preparing emulsion concentrates; Antioxidants such as ascorbic acid, sodium sulfite, sodium pyrosulfite and sodium bisulfite which are hydrophilic, such as lipophilic tocopherol, dibutylhydroxytoluene and butylhydroxyanisole, to ensure the stability of the emulsion concentrate; And a pH-adjusting agent to adjust the pH to 5.0-7.0. A stable composition containing coenzyme Q10 and a statin-based drug, characterized in that it is solubilized by adding an acidifying agent, citric acid, succinic acid, tartaric acid, formic acid and malic acid. It relates to a soft capsule formulation containing as a component.

In the composition of the present invention, the active ingredients are preferably not more than 1 to 20% by weight, respectively. If the active ingredient is included in more than 20% by weight solubility is sharply lowered, such as precipitation during storage or content may be poor stability, and if the active ingredient is added in less than 1% by weight of the total weight solubility and There is a disadvantage that the stability is increased but the dosage can be increased.

In addition, the surfactant is suitably about 10 to 70% by weight relative to the total weight, the particle size is very large when less than 10% by weight is used, the particle size is small when more than 70% by weight is added, soft When molded into capsules, gelatin bonding is poor, and leakage of contents may occur in terms of adhesion during storage. If this occurs, it is not preferable because the cost of new equipment investment, such as additional equipment to the soft capsule molding equipment is generated.

The soft capsule film in the present invention was prepared by a conventional film production method using a general soft capsule manufacturing component containing a known gelatin, plasticizer. The coating composition includes 118 mg of gelatin, 32.8 mg of glycerin, 14.1 mg of sorbitol solution, 0.7 mg of ethyl vanillin, 0.35 mg of methyl paraoxybenzoate, 0.05 mg of paraoxybenzoate, etc. per capsule (166 mg).

Production of soft capsules of coenzyme Q10 and statin drug of the present invention is molded into Oval # 6 by a conventional filling method using a rotary automatic charger, which is generally used, and then dried and screened to a prototype. do.

The soft capsule prepared by the present invention was superior to the statin drug prepared by the general manufacturing process. In addition, the dissolution rate of coenzyme Q10, which can reduce the side effects of statin drugs, also showed excellent results. Therefore, according to the present invention can be provided a formulation having an excellent dissolution rate to solve the side effects of statin-based drugs.

In addition, the solid preparation of the present invention is 0.4 to 9% by weight of coenzyme Q10 relative to the total weight; 0.4-9% by weight of statin-based drug; Solubilizer corresponding to 4.5 to 32% by weight; Surfactant corresponding to 4.5 to 32% by weight; Cosurfactants corresponding to 4.5 to 32% by weight; Oils corresponding to 0.4 to 9% by weight; Antioxidant corresponding to 0.04-9% by weight; Coenzyme Q10 and a statin-based drug-containing nanoemulsion comprising a pH adjuster corresponding to 0.04-2.3 wt%; Wet granulated with about 1-50% by weight of one or more excipients or binders selected from lactose, microcrystalline cellulose, starch, hydroxypropylmethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose and then dried; About 0.1 to 5.0% by weight of one or more lubricants selected from magnesium stearate, talc, stearic acid, and hard silicon dioxide by post-mixing; And 0.1-20% by weight of one or more disintegrants selected from crospovidone, pregelatinized starch, dried starch, sodium starch glyconate, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and then mixed with tablets or hard capsules. It is filled into an oral solid preparation.

In the composition of the present invention, the coenzyme Q10 and the statin-based drug each have a suitable concentration in the range of about 1 to 20% by weight, and the tablet is too large at less than 1% by weight, and the amount of excipient is relatively too small at more than 20% by weight, thereby forming the tablet. This is impossible.

If the amount of the lubricant is greater than 5.0% by weight, the disintegration may be further delayed. If the amount of the lubricant is less than the 0.1% by weight range, there is no lubricant effect. In addition, when the disintegrant is less than 0.1% by weight, the disintegration rate is slow, and when the disintegrant is more than 20% by weight, it is easy to disintegrate itself by convention and the size of the tablet is also increased.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

[Examples 1-3]

Among the components shown in Table 1, the other ingredients except coenzyme Q10 and statin-based drugs, oils, and antioxidants were heated to a temperature of about 50-70 ° C., thoroughly mixed, stirred until clear, and then oils were added. Stir in the same way and mix thoroughly. Subsequently, the coenzyme Q10 and the statin-based drug, which are the main components, were gradually added to the previously prepared mixed solution at a temperature of about 50 ° C. to completely dissolve it. An aqueous solution of the emulsion phase was prepared. Table 1 shows the compositions used in Examples 1-3.

[Examples 4-6]

Among the components shown in Table 1, the other ingredients except coenzyme Q10 and statin-based drugs, oils, and antioxidants were heated to a temperature of about 50-70 ° C., thoroughly mixed, stirred until clear, and then oils were added. Stir in the same way and mix thoroughly. Then, at a temperature of about 50 ° C., coenzyme Q10 and statin-based drug were gradually added to the previously prepared mixture to completely dissolve it, and then added with 20% citric acid-polyethylene glycol (w / v) to an emulsion and excipient adjusted to pH 6.7. Dry after wet granulation. A disintegrant and a lubricant were added to the dried granules, mixed, and a composition for preparing a tablet was prepared. The compositions used in Examples 4-6 are shown in Table 1.

Table 1 Preparation of soft capsules and tablets containing coenzyme Q10 and statins

Ingredient Name Example (unit: mg) One 2 3 4 5 6 Coenzyme Q10 chief ingredient 20 20 20 20 20 20 Simvastatin chief ingredient 20 20 Atorvastatin calcium chief ingredient 20 20 Rochevastatin Calcium chief ingredient 20 20 Propylene glycol Melting aid 119.3 119.3 79.3 119.3 119.3 79.3 Polyethylene Glycol 400 Melting aid 70 100 140 70 100 140 Twin 20 Surfactants 80 50 50 80 50 50 Oleic acid oil 50 50 50 50 50 50 Tocopherol Antioxidant 10 10 10 10 10 10 Citric acid pH adjuster 0.7 0.7 0.7 0.7 0.7 0.7 Microcrystalline cellulose Excipient 427 427 427 Lactose Excipient Croscarmellose sodium Disintegrant 10 10 10 Magnesium stearate Lubricant 3 3 3 Sum 370 370 370 810 810 810

 [Comparative Example 1]

20 mg of coenzyme Q10, 20 mg of simvastatin, 370 mg of microcrystalline cellulose, 370 g of lactose, 15 mg of croscarmellose sodium, 5 mg of magnesium stearate were mixed for 5 minutes, and then compressed into tablets.

[Comparative Example 2]

20 mg of coenzyme Q10, 20 mg of atorvastatin calcium, 370 mg of microcrystalline cellulose, 370 mg of lactose, 15 mg of croscarmellose sodium, 5 mg of magnesium stearate were mixed for 5 minutes, and then compressed into tablets.

[Comparative Example 3]

Coenzyme Q10 20mg, Rochevastatin calcium 20mg, microcrystalline cellulose 370mg, lactose 370mg, croscarmellose sodium 15mg, magnesium stearate 5mg mixed and mixed for 5 minutes to prepare a tablet.

Experimental Example

Dissolution Rate Test and Comparative Evaluation

The soft capsule formulation of coenzyme Q10 and statin-based drugs prepared in Example 13 and the tablets of coenzyme Q10 and statin-based drugs prepared in Example 46, and Comparative Example 13 were subjected to the dissolution test under the following operating conditions. The results are shown in Table 25 and FIG. 14.

<Elution test condition of coenzyme Q10>

Dissolution test method: Korean Pharmacopoeia 2 method

Eluent: Purified Water

Eluent Temperature: 37 ℃

Rotational Speed: 50rpm

Analytical conditions: The eluate was taken at 5, 10, 15, 30, 45 and 60 minutes after the start of the dissolution test. The solution was filtered using a 0.45 μm membrane filter as a sample solution and measured at a wavelength of 275 nm using HPLC.

<Elution test condition of simvastatin>

It was tested using Simvastatin dissolution test method and purified water described in USP.

Eluent Temperature: 37 ℃

Dissolution Method: Paddle Method

Eluate: water alone or sodium lauryl sulfate in 900 milliliters of 0.01 M sodium phosphate buffer (pH 7.0)

Analytical conditions: Eluate was taken at 5, 10, 15, 30, 45 and 60 minutes after the start of the dissolution test. The solution was filtered using a 0.45 μm membrane filter as a sample solution and measured at wavelength of 238 or 247 nm using HPLC. It was.

<Elution test conditions of atorvastatin calcium>

The dissolution test of atorvastatin calcium was tested according to the dissolution test method of the company standard.

Dissolution test method: Korean Pharmacopoeia 2 method

Eluent: Purified Water

Eluent Temperature: 37 ℃

Analytical conditions: The eluate was taken at 5, 10, 15, 30, 45 and 60 minutes after the start of the dissolution test. The solution was filtered using a 0.45 μm membrane filter as a sample solution and measured at a wavelength of 244 nm using HPLC.

<Elution test conditions of Roschvastatin calcium>

The dissolution test of roschvastatin calcium was tested according to the dissolution test method of the company standard.

Eluent Temperature: 37 ℃

Dissolution Method: Paddle Method

Eluent: Water alone or sodium lauryl sulfate in 900 milliliters of 0.05M Citrate buffer (pH 6.6)

Analytical conditions: The eluate was collected at 5, 10, 15, 30, 45 and 60 minutes after the start of the dissolution test. The solution was filtered using a 0.45 μm membrane filter as a sample solution and measured at a wavelength of 238 nm using HPLC.

TABLE 2 Coenzyme Q10 Dissolution Test Results in Water

Dissolution time (minutes) Dissolution rate (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 5 75.4 70.8 74.1 20.4 15.2 18.5 2.1 2.0 2.2 10 86.6 81.2 82.8 68.3 61.1 66.7 2.4 2.1 2.3 15 94.5 89.6 91.9 80.8 77.9 78.0 3.5 3.4 3.2 30 98.4 99.1 98.4 95 96.3 94.1 5.7 5.5 5.8 45 100.1 99.5 99.7 100 99.0 98.3 5.8 6.1 6.2 60 100.3 101.0 99.9 100 99.8 99.7 7.1 7.5 7.4

TABLE 3 Simvastatin Dissolution Test Results in Water

Dissolution time (minutes) Dissolution rate (%) Example 1 Example 4 Comparative Example 1 5 60.4 20.0 5.4 10 75.7 35.2 10.8 15 87.2 58.3 18.2 30 97.2 92.6 33.5 45 99.3 97.3 45.1 60 100.1 99.7 58.9

Table 4 Results of atorvastatin calcium dissolution test in water

Dissolution time (minutes) Dissolution rate (%) Example 2 Example 5 Comparative Example 2 5 58.2 23.1 2.0 10 80.5 36.7 2.4 15 91.4 61.3 3.4 30 97.3 89.9 5.7 45 99.7 98.8 6.1 60 100.2 99.7 6.3

[Table 5] Results of roschvastatin calcium dissolution test in water

Dissolution time (minutes) Dissolution rate (%) Example 3 Example 6 Comparative Example 9 5 65.3 19.3 2.2 10 77.3 40.2 2.3 15 89.7 69.8 3.1 30 98.3 94.7 4.0 45 100.1 99.6 4.4 60 100.3 100.2 5.1

1 is a graph showing coenzyme Q10 dissolution test results of coenzyme Q10 and a statin-based drug preparation prepared according to Example 16 and Comparative Example 13. FIG.

Figure 2 is a graph showing the simvastatin dissolution test results of coenzyme Q10 and statin-based drug-containing preparation prepared according to Examples 1, 4 and Comparative Example 1.

Figure 3 is a graph showing the results of atorvastatin calcium dissolution test of coenzyme Q10 and statin-containing formulations prepared according to Examples 2, 5 and Comparative Example 2.

Figure 4 is a graph showing the results of the Roschvastatin calcium dissolution test of coenzyme Q10 and statin-containing formulations prepared according to Examples 3, 6 and Comparative Example 3.

Claims (6)

A pharmaceutical composition comprising a nanoemulsion containing coenzyme Q10, a statin drug, a dissolving agent, a surfactant, oils, an antioxidant, and a pH adjusting agent, Nanoemulsion contains coenzyme Q10 and statin drug in the same weight, A pH adjusting agent is 0.1 to 5% by weight relative to the total weight of the nanoemulsion, the pH of the nanoemulsion is a pharmaceutical composition comprising coenzyme Q10 and statin-based drug-containing nanoemulsion, characterized in that the pH is adjusted to 5.0 ~ 7.0. The coenzyme Q10 and statin drug-containing nanoemulsion according to claim 1, wherein the solubilizer is at least one member selected from the group consisting of polyethylene glycol, propylene glycol, triacetin, glycerol and diethylene glycol monoethyl ether. Pharmaceutical compositions. The pharmaceutical composition of claim 1, wherein the oils are oleic acid. Coenzyme Q10 and a statin-based drug-containing nanoemulsion. The method of claim 1, wherein the antioxidant is characterized in that at least one selected from the group consisting of tocopherol, dibutyl hydroxytoluene, butyl hydroxyanisole, ascorbic acid, sodium sulfite, sodium pyrosulfite, and sodium bisulfite. A pharmaceutical composition comprising coenzyme Q10 and a statin-based drug-containing nanoemulsion. The pharmaceutical composition of claim 1, wherein the pH adjusting agent is at least one selected from the group consisting of citric acid, succinic acid, tartaric acid, formic acid, and malic acid. 2. The pharmaceutical composition comprising coenzyme Q10 and a statin-based drug-containing nanoemulsion according to claim 1, wherein the statin-based drug is simvastatin, atorvastatin calcium or roschvastatin calcium.

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