KR100918325B1 - Pharmaceutical combination preparations for hypercholesterolemia and process for preparing the same - Google Patents

Abstract

The present invention relates to a combination preparation for treating hypercholesterolosis, and more particularly, a statin compound as a first active ingredient and coenzyme Q ₁₀ as a second active ingredient. And one selected from the group consisting of poloxamer, tocopheryl polyethylene glycol succinate and fatty acid glycerol ester as absorption enhancers. It relates to a combination preparation for treating hypercholesterolosis.

As the co-formulation of the present invention is a poorly soluble drug, the solubility and dissolution properties of HMG-CoA reductase inhibitor and coenzyme Q ₁₀ with very low absorption are significantly improved, and by including a statin compound and coenzyme Q ₁₀ in one single dosage form, Minimizing the side effects of using a statin compound and having a synergistic effect on the treatment of cardiovascular diseases, there is an advantage that can improve the convenience and dosage compliance.

Statin Compound, Coenzyme Q10, Poloxamer, Co-Formulation, Single-Dose

Description

Pharmaceutical combination preparations for hypercholesterolemia and process for preparing the same}

1 shows chemical structures of various statin compounds.

Figures 2a, 2b, 2c and 2d shows the results of differential calorimetry measurement of the atorvastatin calcium, coenzyme Q ₁₀ , the solid dispersion and the physical mixture of Example 16.

3a, 3b, 3c and 3d show the results of X-ray diffraction measurements on the solid dispersion and physical mixture of atorvastatin calcium, coenzyme Q ₁₀ , Example 16.

Figure 4 shows the dissolution curve of the statin compound in the combination preparation of the present invention.

Figure 5 shows the dissolution curve of coenzyme Q ₁₀ in the co-formulation of the present invention.

The present invention relates to a combination preparation for treating hypercholesterolosis, and to a combination preparation for treating hypercholesterolosis, which has improved side effects due to the use of a statin compound, which is an HMG-CoA reductase inhibitor.

Statin compounds are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which effectively treat hypercholesterolosis and are effective in various cardiovascular diseases including atherosclerosis caused by hypercholesterolemia. It is an effective treatment.

HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid, a sterol precursor containing cholesterol, and statin compounds effectively inhibit cholesterol synthesis in the body by inhibiting the action of HMG-CoA reductase. In the cholesterol synthesis pathway, HMG-CoA reductase catalyzes the conversion of HMG-CoA, a rate determining step for cholesterol biosynthesis, to the sterol precursor mevalonic acid.

Figure 1 shows the structure of HMG-CoA and the chemical structure of some statin compounds that are HMG-CoA reductase inhibitors. The statin compounds basically have a HMG structure. Simvastatin and lovastatin have lactone rings instead of these structures, but they are converted to the HMG structure, which is the active form of the biologically open ring in the human body, and other statin compounds are administered in the open ring form. New statin compounds of the HMG structure have a higher affinity for HMG-CoA reductase has been demonstrated to have a greater inhibitory effect. Enzymatic activity experiments of the HMG-CoA reductase substrate catalyst portion showed that statins, including simvastatin, flavastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, had high affinity with HMG-CoA reductase Showed that all statins could inhibit this enzyme [Science 2001, 292, 1160-1164; Biochemical Society transactions 2003, 31, 528-531.

As described above, the statin compound inhibits the action of HMG-CoA reductase to prevent cholesterol synthesis in the liver and increases LDL receptors on the surface of hepatocytes to promote LDL absorption and metabolism, thereby effectively treating hypercholesterolemia and hypercholesterolemia. It can be effectively used for cardiovascular diseases including atherosclerosis caused by.

However, statin compounds have a number of side effects, including hepatotoxicity, muscle damage, cancer, visual field damage, hair loss and reduced production of bioavailable substances in some of the patients taking them. Detailed mechanisms are not well known, but have been reported to directly induce mytoxicosis and impair immune function by inhibiting HMG-CoA reductase [JAMA: the journal of the American Medical Association 2003, 289, 1681-1690. ]. In particular, the occurrence of serious side effects, such as rhabdomyolysis or myopathy, may lead to discontinuation of the drug. Cholesterol is used as a precursor to steroid hormones, and because it plays an important role in maintaining normal cellular function, inhibition of cholesterol synthesis by statins can damage cells and cause cell membrane instability.

Inhibition of HMG-CoA reductase directly reduces the synthesis of farnesyl pyrophosphate, a coenzyme Q ₁₀ metabolic intermediate. Coenzyme Q ₁₀ is a steroid isoprenoid that plays an important role as a cellular energy transporter in the mitochondrial electron transport system. In addition, fat-soluble coenzyme Q ₁₀ is used for ATP synthesis in the inner membrane of mitochondria, stabilizes the cell membrane with a carrier of electrons and hydrogen ions, maintains cellular function and has a function as a powerful antioxidant. Co-depletion of cholesterol and coenzyme Q ₁₀ with statins reduces energy metabolism (ATP synthesis), a key role of coenzyme Q ₁₀ , particularly affecting muscle tissues that require high energy. Decreased coenzyme Q ₁₀ is a major cause of myxotoxicity. Actual decreases in serum coenzyme Q ₁₀ have been reported in patients with myofascial atrophy and malnutrition, and myopathy has been linked to muscle coenzyme Q ₁₀ deficiency. Archives of neurology 2005, 62, 317-320.

50% of the total coenzyme Q _{10 in} the human body is internally synthesized but serum coenzyme Q _{10 in} patients taking statins The levels were relatively low and a decrease in coenzyme Q ₁₀ was observed in patients taking high concentrations of simvastatin [Clinical pharmacology and therapeutics 1995, 57, 62–66; 2005, 78, 60-64. In addition, an increase in the ratio of pyruvate to lactic acid in patients taking statins suggests that mitochondrial dysfunction has occurred [The Journal of clinical pharmacology 1996, 42, 333-337], although intracellular coenzyme Q ₁₀ levels are measured. However, biological samples from patients with statin-induced muscle disease have been shown to impair mitochondrial function [Annals of internal medicine 2002, 137, 581-585].

Thus, co-administration of statins and coenzyme Q ₁₀ can reduce cholesterol levels in patients and effectively reduce the side effects of statin administration.

US 2004/0063661 A1 discloses therapeutic combinations comprising coenzyme Q ₁₀ , uridine in the treatment of side effects by statin compounds. Therefore, it is desirable to formulate a co-formulation of two active substances in coenzyme Q ₁₀ that can inhibit the side effects to patients in need of treatment of statin compounds.

However, in such co-formulation, poor solubility of coenzyme Q ₁₀ and statin compounds becomes a problem. In particular, coenzyme Q ₁₀ is hardly soluble in water, and its solubility at room temperature is extremely low, about 5 ug / mL or less. Various formulations have been attempted to improve low dissolution properties and bioavailability due to the low solubility of coenzyme Q ₁₀ . US Patent No. 6,056,971 discloses a copolymer mixture of sorbitan fatty acid esters, sorbitol oleate esters, and (poly) ethylene oxides in polyhydric alcohols as a dissolving agent to improve the elution properties and bioavailability of coenzyme Q ₁₀ . The method of making is disclosed. However, the method is complicated and can only produce a liquid formulation, which makes it difficult to apply to tablets which are common dosage forms.

The present inventors have studied to solve the above problems, and as a result, the statin compound and coenzyme Q ₁₀ can be formulated in a stable single dosage form, and have a much higher bioavailability than when each therapeutic agent is administered in a separate dosage form. The present invention was found to complete the present invention.

It is an object of the present invention to eliminate and ameliorate the side effects in patients in need of statin compound treatment, and to provide a synergistic effect on the treatment of cardiovascular diseases, a single administration of two pharmaceutical substances of statin compound and coenzyme Q ₁₀ It can be administered in the form, and to provide a stable combination formulation having excellent bioavailability.

It is also an object of the present invention to provide a stable and long term storeable formulation with low levels of impurities and / or degradation products which may occur between the preparation of the composition and / or subsequent storage.

In order to achieve the above object, the present invention provides a statin compound as the first active ingredient and coenzyme Q ₁₀ as the second active ingredient. And one selected from the group consisting of poloxamer, tocopheryl polyethylene glycol succinate and fatty acid glycerol ester as absorption enhancers. Provided is a combination preparation for treating hypercholesterolemia.

Hereinafter, the present invention will be described in more detail.

The co-formulation of the present invention may be administered in one single dosage form, including a statin compound as the first active ingredient and coenzyme Q ₁₀ as the second active ingredient, wherein the active ingredients are mixed at an optimal ratio to form a complex, Thus, by including poloxamer as an absorption enhancer, solubility and dissolution properties are improved, thereby improving bioavailability of each active ingredient, which can be effectively used to treat hypercholesterolemia while minimizing side effects of statin compounds.

In the co-formulation of the present invention, the statin compound as the first active ingredient is atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, HR-780, GR-95030, CI 980, B My 22089, B My 22566, XU-62-320 and the like can be used, more preferably atorvastatin or simvastatin, and most preferably atorvastatin.

In the co-formulation of the present invention, the second active ingredient, coenzyme Q ₁₀ is represented by the following formula (1), also referred to as ubiquinone.

[Formula 1]

In the present invention, the statin compound and coenzyme Q ₁₀ is used in a weight ratio of 1: 0.2 to 1:30. If the ratio is less than 1: 0.2, the dosage of coenzyme Q ₁₀ may not be sufficient to achieve a therapeutic effect.If the ratio is greater than 1:30, the volume of the tablet may increase, which may make it difficult to administer the drug. There is a problem in tableting. Preferably it is 1: 1-1: 10, More preferably, it is 1: 3-1: 9, Most preferably, it is 1: 3. More specifically, when the HMG-CoA reductase inhibitor is atorvastatin, the ratio of atorvastatin to coenzyme Q ₁₀ ranges from 1: 0.2 to 1:30. For example, when atorvastatin and coenzyme Q ₁₀ is 1: 3, it includes coenzyme Q ₁₀ 30 mg / day along with atorvastatin ₁₀ mg / day. Also, for example, when atorvastatin and coenzyme Q ₁₀ is 1:20, atorvastatin 20 mg / day is administered with coenzyme Q ₁₀ 400 mg / day. The ratio of atorvastatin to coenzyme Q ₁₀ is in the range of 1: 1 to 1:10. Atovastatin and simvastatin are appropriate for HMG-CoA reductase inhibitors in the weight ratios of the components described herein.

In the composite preparation of the present invention, high molecular compounds such as poloxamer, tocopheryl polyethylene glycol succinate (TPGS), polyethylene glycol (PEG), fatty acid glycerol ester (gellucire) and the like can be used. Particular preference is given to poloxamers. Poloxamer can improve the dissolution properties and bioavailability by increasing the solubility of the active ingredient HMG-CoA reductase inhibitor and coenzyme Q ₁₀ together. The poloxamers of the present invention are poloxamers which are polyoxyethylene, polyoxypropylene and methyl-oxirane polymers, preferably poloxamer 407 and poloxamer 188, and more preferably poloxamer 407.

In addition, the coenzyme Q ₁₀ and poloxamer is preferably 1: 0.1 ~ 1:40 weight ratio. More preferably, it is 1: 0.5-1: 10, Most preferably, it is 1: 3.

The co-formulation of the present invention can administer the statin compound and coenzyme Q ₁₀ in one single dosage form, improve the solubility and dissolution characteristics of each active ingredient, improve the bioavailability of each component, thereby reducing the side effects of the statin compound It can be effectively used to treat hypercholesterolemia while minimizing it. In addition, it can be used safely and continuously for the treatment of various cardiovascular diseases caused by hypercholesterolemia.

The co-formulation of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration. Pharmaceutically acceptable carriers include, for example, saline solution, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, combinations thereof, etc. Other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, such as aqueous solutions, suspensions, emulsions, microemulsions, pills, capsules, granules or tablets. Furthermore, it may be preferably formulated by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA. The co-formulations of the present invention can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally, topically, etc.) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the condition, diet, administration time, administration method, excretion rate and severity of the disease. Daily dosages are prepared in the same range of content contained in conventional statin compound formulations. However, the dosage of the co-formulation according to the present invention may be appropriately selected depending on the route of administration, subject to administration, age, gender, weight, individual difference and disease state. As long as the effect according to the present invention is exhibited, the formulation, route of administration and administration method are not particularly limited.

Hereinafter, the preparation method of the composite preparation of the present invention will be described in detail.

The co-formulation of the present invention simply mixes each component or melts each component at a certain temperature and then mixes (melting method), another method dissolves each component in a specific solvent and then evaporates the solvent ( Organic solvent evaporation method), or a combination of the above methods. In particular, in the case of preparing each component in the form of a solid dispersion by melting or dissolving it in a solvent, each active ingredient, particularly coenzyme Q _10, is effectively eluted from the formulation, and thus high bioavailability is preferable. In this case, the solvent may be any solvent capable of dissolving the compositional components of the present invention. Preferably, methanol, ethanol, methylene chloride, chloromethane, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, isopropanol and the like or a mixed solvent thereof may be used, and most preferably ethanol is used. .

In addition, the co-formulation of the present invention may be formulated in the form of granules, capsules, tablets, emulsions, micro emulsions and the like. Tablets containing the co-formulation of the present invention may be preferably prepared as follows.

a) dissolving an absorption enhancer such as poloxamer in a solvent, followed by mixing and dissolving coenzyme Q ₁₀ ;

b) mixing the statin compound dissolved in a separate solvent;

c) granulating by adding microcrystalline cellulose and silicic anhydride, drying and pulverizing to 14-35 mesh to obtain granules; And

d) mixing and tableting the disintegrant, binder and glidant.

In the above step, the solvent may be any solvent capable of dissolving the composition components of the present invention as described above, and preferably ethanol is used. The temperature of the step is preferably 45 ~ 55 ℃. At this time, if the size of the granules is less than 14 mesh, the content is irregular and not preferable, and when the size of the granules exceeds 35 mesh, the tableting performance is poor, which is not preferable.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

<Examples 1 to 10> Preparation of solid dispersions for each type of polymer

Next, 1 g of each polymer of Table 1 was dissolved at a melting point or higher, and coenzyme Q ₁₀ (Daewoong Pharm) was added and then dissolved at 45 to 55 ° C. Separately, after mixing and dissolving atorvastatin (milk emulsion) dissolved in ethanol to prepare a solid dispersion. On the other hand, it was simply mixed in the composition of the above table to obtain a physical mixture.

TABLE 1

Example drug Polymer One 1 g of atorvastatin Coenzyme Q ₁₀ 1 g Poloxamer 188 1g 2 Poloxamer 338 1g 3 Poloxamer 407 1g 4 TPGS 1g 5 PEG 4000 1g 6 PEG 6000 1g 7 Gelushire 39/01 1g 8 Gelushire 43/01 1g 9 Gelushire 44/14 1g 10 Gelushire 50/13 1g

<Comparative Examples 1 to 10> Preparation of solid dispersions by polymer type according to statin drugs

Next, 1 g of each polymer in Table 2 was dissolved at a melting point or higher, and separately mixed with atorvastatin dissolved in ethanol to prepare a solid dispersion. On the other hand, it was simply mixed in the composition of the above table to obtain a physical mixture.

TABLE 2

Comparative example drug Polymer One 1 g of atorvastatin Poloxamer 188 1g 2 Poloxamer 338 1g 3 Poloxamer 407 1g 4 TPGS 1g 5 PEG 4000 1g 6 PEG 6000 1g 7 Gelushire 39/01 1g 8 Gelushire 43/01 1g 9 Gelushire 44/14 1g 10 Gelushire 50/13 1g

<Comparative Examples 11-20> Preparation of solid dispersions according to types of polymers according to coenzyme Q ₁₀ drug

Next, 1 g of each polymer in Table 3 was dissolved at a melting point or higher, and coenzyme Q ₁₀ was dissolved in the melted polymer to prepare codiszyme Q ₁₀ at a predetermined temperature, thereby preparing a solid dispersion. On the other hand, it was simply mixed in the composition of the above table to obtain a physical mixture.

TABLE 3

Comparative example drug Polymer 11 Coenzyme Q ₁₀ 1 g Poloxamer 188 1g 12 Poloxamer 338 1g 13 Poloxamer 407 1g 14 TPGS 1g 15 PEG 4000 1g 16 PEG 6000 1g 17 Gelushire 39/01 1g 18 Gelushire 43/01 1g 19 Gelushire 44/14 1g 20 Gelushire 50/13 1g

Experimental Example 1 Measurement of Solubility of Solid Dispersions by Types of Polymers According to Two Drugs

120 mg of the solid dispersion prepared in Examples 1 to 10 and the physical components obtained by mixing each component were added to 4 mL of water, dissolved for 30 minutes by ultrasound, and left for 48 hours at 37 ° C., followed by 0.45 μm. After filtration with a filter, the amount of atorvastatin and coenzyme Q ₁₀ drug in the solution was measured using HPLC, and the results are shown in Tables 4 to 5 below.

TABLE 4

division Atorvastatin solubility (μm / mL) Physical mixing Solid dispersion Example One 173.7 425.5 2 277.0 309.1 3 326.2 424.0 4 661.1 995.5 5 155.1 187.2 6 156.6 196.0 7 157.5 211.4 8 178.9 259.3 9 866.0 1224.3 10 416.4 560.1

TABLE 5

division Coenzyme Q ₁₀ Solubility (μm / mL) Physical mixing Solid dispersion Example One 20.8 992.9 2 29.4 1408.3 3 44.3 1938.8 4 37.1 313.1 5 1.1 15.4 6 1.6 18.4 7 3.7 16.3 8 13.9 13.5 9 90.2 155.8 10 5.8 313.4

Experimental Example 2 Measurement of Solubility of Solid Dispersions by Type of Polymer According to Statin Drugs

80 mg of the solid dispersion and the physical mixture prepared in Comparative Examples 1 to 10 were added to 4 mL of water, dissolved in ultrasonic waves for 30 minutes, left at 37 ° C. for 48 hours, and filtered through a 0.45 μm filter. The amount of statin drug in the solution was measured using HPLC, and the results are shown in Table 6 below.

TABLE 6

division Solubility (μm / mL) Physical mixing Solid dispersion Comparative example One 183.2 469.6 2 272.5 307.7 3 303.4 397.1 4 714.7 993.9 5 155.2 190.1 6 152.9 197.2 7 170.2 207.5 8 190.0 230.7 9 839.6 1143.7 10 424.6 566.4

Experimental Example 3 Measurement of Solubility of Solid Dispersions by Type of Polymer According to Coenzyme Q ₁₀ Drug

80 mg of the solid dispersion and the physical mixture prepared in Comparative Examples 11 to 20 were added to 4 mL of water, dissolved in ultrasonic waves for 30 minutes, left at 37 ° C. for 48 hours, and then filtered through a 0.45 μm filter. The amount of coenzyme Q ₁₀ drug in the solution was measured using HPLC, and the results are shown in Table 7 below.

TABLE 7

division Solubility (μm / mL) Physical mixing Solid dispersion Comparative example 11 7.9 130.2 12 7.6 198.7 13 27.0 170.0 14 6.3 18.9 15 0.7 18.1 16 0.3 13.6 17 0.8 0.3 18 2.4 0.4 19 58.0 125.2 20 11.0 58.7

As shown in Tables 4 to 7, the solubility in the solid dispersion of the present invention showed the largest increase in coenzyme Q ₁₀ when mixed with poloxamers. In addition, it can be seen that the solubility of the drug is significantly increased when the polymer and both drugs are mixed than when the polymer and one drug are mixed.

<Examples 11 to 15> Preparation of physical mixtures according to the content of the polymer

In order to determine the solubility of each active ingredient according to the content of the polymer, it was weighed according to the composition of Table 8 and prepared by simple mixing (physical mixing).

TABLE 8

Example drug Polymer 11 Atorvastatin 10mg Coenzyme Q ₁₀ 10mg Poloxamer 407 4 mg 12 Poloxamer 407 10 mg 13 Poloxamer 407 20 mg 14 Poloxamer 407 30 mg 15 Poloxamer 407 40 mg

<Comparative Example 21-25>

Prepared by weighing and simple mixing according to the composition of Table 9.

TABLE 9

Comparative example drug Polymer 21 Atorvastatin 10mg Poloxamer 407 4 mg 22 Poloxamer 407 10 mg 23 Poloxamer 407 20 mg 24 Poloxamer 407 30 mg 25 Poloxamer 407 40 mg

<Comparative Example 26-30>

It prepared using the following polymer in the same manner as in the composition and Example 2 of Table 10.

TABLE 10

Comparative example drug Polymer 26 Coenzyme Q ₁₀ 10mg Poloxamer 407 4 mg 27 Poloxamer 407 10 mg 28 Poloxamer 407 20 mg 29 Poloxamer 407 30 mg 30 Poloxamer 407 40 mg

Experimental Example 4 Measurement of Solubility of Physical Mixture by Content of Polymer

4 mL of water was added to each of the physical mixtures prepared in Examples 11 to 15 and Comparative Examples 21 to 30, dissolved in ultrasound for 30 minutes, left at 37 ° C. for 48 hours, and filtered through a 0.45 μm filter, followed by HPLC. The amount of atorvastatin and coenzyme Q ₁₀ drug in the solution was measured, and the results are shown in Tables 11 to 12, respectively.

TABLE 11

division Solubility (μm / mL) Example 11 190.5 12 219.1 13 248.7 14 286.6 15 326.2 Comparative example 21 157.9 22 168.6 23 212.8 24 245.2 25 303.4

TABLE 12

division Solubility (μm / mL) Example 11 5.5 12 16.1 13 22.1 14 31.2 15 44.3 Comparative example 26 0.3 27 0.8 28 3.7 29 19.6 30 27.0

As shown in Tables 11 to 12, the co-formulation of the present invention is coenzyme Q ₁₀ And coenzyme Q _{10 as an} active ingredient, as compared to comparative examples in which a statin compound is mixed with poloxamer, respectively. And it can be seen that the solubility of the statin compound is significantly increased.

<Example 16>

Atorvastatin 10mg, Coenzyme Q ₁₀ 30 mg _, 90 mg of poloxamer 407 were weighed, and a solid dispersion was obtained by the method of Example 1. On the other hand, the mixture was simply mixed to obtain a physical mixture.

Experimental Example 5 DSC (Differential Scanning Calorimeter) Measurement Results

The atorvastatin calcium, coenzyme Q ₁₀ raw material and the solid dispersion of Example 16 and its physical mixture were measured by differential scanning calorimetry (model name: S-650, manufacturer-manufacturer: Scinco, Ltd., Korea), respectively. 2b, 2c and 2d. As can be seen in Figure 2c and 2d, in the composition of the present invention it can be seen that the crystalline atorvastatin original is changed to amorphous, and the coenzyme Q ₁₀ original is interacting with poloxamer 407.

Experimental Example 6 XRD (X-ray Diffraction) Measurement Results

X-ray diffraction patterns of the atorvastatin calcium, coenzyme Q _{10 original} and the solid dispersion of Example 16 and the physical mixture thereof were measured (model name: D / MAX-2200 Ultima / PC, manufacturer-manufacturer: Rigaku Co., Japan), respectively, shown in FIGS. 3A, 3B, 3C, and 3D. As can be seen in Figure 3d, it can be seen that the crystalline atorvastatin raw material is changed to amorphous, and the coenzyme Q ₁₀ raw material produced a solid dispersion having reduced crystallinity.

Preparation Example 1 Preparation of Uncoated Tablets

After weighing each of the components in the composition and content shown in Table 13, the poloxamer 407 was warmed at a temperature of about 50 ℃ and dissolved, and then coenzyme Q ₁₀ was added to completely dissolve around 50 ℃. After mixing atorvastatin dissolved in ethanol, microcrystalline cellulose and silicic anhydride were added, mixed, stipulated, dried at room temperature and ground to 14 to 35 mesh to obtain granules. Uncoated tablets were prepared by mixing and tableting the following excipients, binders, and lubricants with the granules.

TABLE 13

Ingredient Name 1 tablet (mg) 100 tablet (g) Coenzyme Q ₁₀ 30 3 Atorvastatin calcium 10.845 1.084 Poloxamer 407 90 9 Microcrystalline cellulose 125 12.5 Lactose 81.155 8.116 Croscarmellose sodium 50 5 Silicic anhydride 10 One Magnesium stearate 3 0.3 ethanol Quantity Quantity

Experimental Example 7 Dissolution Test

Uncoated tablet prepared in Preparation Example 1, Coenzyme Q ₁₀ as a control The dissolution test was performed on Lipitor ^® as a comparative control for the raw material powder of atorvastatin and atorvastatin. The dissolution test was based on USP XXVII (paddle method, 50 rpm) and using 900 mL of distilled water (37 ° C., 1% polysorbate 80). Take 1 mL of the sample and filter it with 1.2 um syringe filter (MILLIPORE), and measure the concentration of each active ingredient by HPLC, and the release amount according to the time is atorvastatin coenzyme Q ₁₀ in FIG. Is shown in FIG.

As shown in Figure 4 and 5, the co-formulation of the present invention is coenzyme Q ₁₀ of the active material And it can be seen that atorvastatin exhibits a much faster dissolution rate than the control (raw material), thereby confirming that the combination preparation of the present invention can elute each active ingredient faster to improve bioavailability.

Preparation Example 2 Preparation of Micro-Emulsion

To prepare a microemulsion with the composition and content shown in Table 14-15. That is, after co-surfactant, oil components and surfactants are uniformly mixed, and gently warmed to a temperature of about 60 ℃, atorvastatin and coenzyme Q ₁₀ is added and stirred to dissolve the resulting concentrate as it is or if necessary It was prepared according to a conventional method in a capsule maker by adding a pharmaceutically acceptable additive commonly used in the preparation of capsules.

TABLE 14

division Preparation Example (mg) One 2 Coenzyme Q ₁₀ 30 30 Atorvastatin 10 10 Propylene carbonate 150 200 Conjugated linoleic acid 150 150 Polyoxyethylene (20) sorbitan monolaurate 100 120 Polyoxyethylene (35) hydrogenated castor oil 100 30

TABLE 15

division Preparation Example (mg) One 2 Coenzyme Q ₁₀ 30 30 Atorvastatin 10 10 Polyethylene glycol 150 200 Conjugated linoleic acid 150 150 Polyoxyethylene (20) sorbitan monolaurate 100 120 Polyoxyethylene (35) hydrogenated castor oil 100 30

Experimental Example 8 Bioavailability Comparison Experiment

To investigate the in vivo usage of the present invention formulation, in the statin drug ah Toba statin powder concentrate, Example In 16 solid dispersion and the physical mixture of, as compared to the control group to Lipitor ^®, the coenzyme Q ₁₀ drug coenzyme Q ₁₀ powder concentrate The solid dispersion and the physical mixture of Example 16 were subjected to absorption experiments using 5 rats per group.

After suspending each powder in 0.2% carboxymethylcellulose water, each rat was orally administered with 25 mg / kg of atorvastatin and 75 mg / kg of coenzyme Q ₁₀ . After administration, blood was collected at 0.25, 1, 2, 3, 4, 6, and 8 hours, centrifuged, and plasma was collected, followed by analysis of the amount of two active components in blood using HPLC-MASS, respectively. Statins are shown in Table 16 and coenzyme Q ₁₀ in Table 17.

TABLE 16

parameter Atorvastatin raw powder Compositions of the Invention Lipitor ^® Physical mixture Solid dispersion C _max (ng / mL) 317.8 ± 31.8 414.3 ± 176.3 542.0 ± 152.7 379.7 ± 20.1 T _max (hr) 0.4 ± 0.2 0.8 ± 0.3 1.5 ± 0.3 0.3 ± 0.0 AUC (ng min / mL) 1167.6 ± 203.0 1158.8 ± 280.0 1590.1 ± 374.0 1311.8 ± 62.2

As can be seen in Table 16 above, rats orally administered with atorvastatin-based rats had a C _max of approximately 317.8 ± 31.8 ng / mL and a dose normalized AUC (0-t _last ) value of 1167.6 ± 203.0 ng * min. / mL. On the other hand, the physical mixture and solid dispersion of the present invention resulted in C _max of 1.3 and 1.7 times higher than the original atorvastatin powder, and dose normalized AUC (0-t _last ) values of about 1.0 and 1.4 times higher, respectively. Got.

TABLE 17

parameter Coenzyme Q ₁₀ Raw powder Compositions of the Invention Physical mixture Solid dispersion Cmax (ng / mL) 49.7 ± 13.1 118.5 ± 53.7 289.1 ± 175.0 Tmax (hr) 3.9 ± 0.2 2.8 ± 0.5 2.6 ± 0.4 AUC (ng min / mL) 169.0 ± 28.6 389.8 ± 146.8 854.9 ± 347.6

In addition, as can be seen in Table 17 above, in rats orally administered coenzyme Q ₁₀ , C _max reached approximately 49.7 ± 13.1 ng / mL, and the dose normalized AUC (0-t _last ) value was 169.0 ± 28.6. ng * min / mL. On the other hand, compared to physical mixtures and solid dispersions is coenzyme Q ₁₀ material of the present invention, C _max is was 2.4 and 5.8 times higher, respectively, dose normalized AUC (0-t _last) value is also about respective than in coenzyme Q ₁₀ powder concentrate 2.3 and 5.1 times higher results were obtained. From these results, it can be seen that the composition of the present invention significantly increases the bioavailability of the two active ingredients of poorly soluble drugs.

Experimental Example 9 Storage Stability Test of Tablets

In order to analyze the stability of water and heat for the purification of the solid dispersion prepared in Preparation Example 1 according to the present invention was carried out the following experiment.

The tablets were stored for 3 months, 6 months, 9 months, and 12 months under long-term storage test conditions (25 ° C., 60% RH), and then high-performance liquid chromatography (HPLC) determined the residual rate of initial active ingredient values. Table 16 shows the results of comparing the relative stability measured.

TABLE 18

division Early 3 months 6 months 9 months 12 months Atorvastatin 1.000 0.988 0.992 1.009 0.991 Coenzyme Q ₁₀ 1.000 0.994 0.991 0.984 0.998

As shown in the results of Table 18, the two active ingredient values of the atorvastatin and coenzyme Q10 were included in the deviation, so that even after 12 months, the active ingredient appeared almost the same as the initial one. From this, it was confirmed that the formulation of the present invention has very high storage stability.

Combined preparation of the invention is i the solubility, dissolution characteristics and bioavailability of the very low HMG-CoA reductase inhibitor and coenzyme Q ₁₀ absorb as soluble drug is significantly improved, a statin compound, and coenzyme Q ₁₀ in a single dosage form By including, there is an advantage that can minimize the side effects of the use of the statin compound and improve the convenience and dosage compliance while taking a synergistic effect on the treatment of cardiovascular diseases.

Claims (8)

A composite preparation for treating hypercholesterolosis, comprising a three-component solid dispersion comprising atorvastatin as a first active ingredient, coenzyme Q ₁₀ as a second active ingredient, and poloxamer 407 as an absorption enhancer. delete delete The combination preparation of claim 1, wherein the atorvastatin and coenzyme Q ₁₀ are included in a weight ratio of 1: 0.2 to 1:30. The combination preparation of claim 1, wherein the poloxamer 407 is included in a weight ratio of 0.1 to 40 with respect to coenzyme Q ₁₀ . The combination preparation for treating hypercholesterolosis according to claim 1, which is formulated into granules, capsules or tablets. a) adding poloxamer 407 to an appropriate amount of ethanol, warming to a temperature near 50 ° C., and adding coenzyme Q ₁₀ that is transparent to dissolve, and dissolving completely while maintaining at 48-52 ° C .; b) immediately adding to the coenzyme Q ₁₀ solution of a) the atorvastatin solution separately dissolved in an appropriate amount of ethanol and mixing; c) When the three components are in solution, immediately add microcrystalline cellulose and silicic anhydride, associate for 10 minutes, granulate to 14-20 mesh, dry for 12 hours at 38-42 ° C, and granulate to 16-35 mesh to obtain granules. step; And d) A method for preparing a tablet comprising the three-component solid dispersion of claim 1, which comprises mixing and tableting a disintegrant, a binder, a lubricant, and the like. delete

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