KR100992877B1 - Composition and preparation method of the solid dispersion containing coenzyme Q - Google Patents

Abstract

The present invention provides a solid dispersion of coenzyme Q, which is designed to have excellent solubility and physical stability by including a polyoxyethylene-polyoxypropylene copolymer as a carrier component of the solid dispersion as a solid dispersion containing coenzyme Q. Coenzyme Q is used to treat antioxidants and cardiovascular diseases, but its low solubility results in low bioavailability. Therefore, it is intended to provide a solid dispersion composition and a method for preparing the same, which can improve the solubility of coenzyme Q and thus improve low bioavailability.

Coenzyme Q, solid dispersion, solubility, polyoxyethylene-polyoxypropylene copolymer, silica

Description

Composition and preparation method of the solid dispersion containing coenzyme Q}

The present invention relates to a solid dispersion composition containing coenzyme Q and a method for preparing the same, and more particularly to preparing a solid dispersion composition containing coenzyme Q to improve the solubility of coenzyme Q. By improving bioavailability. In addition, coenzyme Q is present in an amorphous form in the solid dispersion, but recrystallization over time prevents a decrease in solubility, that is, amorphous coenzyme Q is present in the solid dispersion. It relates to a solid dispersion composition designed to have a physical stability.

Coenzyme Q, which is used as an active ingredient in the present invention, is also known as ubiquinone and is a kind of organic compound belonging to the quinone system, which is used not only as an antioxidant but also for the treatment of cardiovascular diseases. (S. Greenberg, WH Fishman, Coenzyme Q ₁₀ : A new drug for cardiovascular disease, J. Clin. Pharmacol. 30 (1990), pp. 590-608) However, due to its very low solubility in water, drug absorption is reduced. Low bioavailability. Because the drug must be dissolved before it can be absorbed through the gastrointestinal membrane. Drugs that do not dissolve are very difficult to pass through the gastrointestinal membrane. It has also been reported that higher drug concentrations in the gastrointestinal tract enhance drug absorption. (T. Maeda, H. Takenaka, Y. Yamahira and T. Noguchi, Use of rabbits for GI drug absorption studies: relationship between dissolution rate and bioavailability of griseofulvin tablets, J. Pharm. Sci. 68 (1979), pp. 1286 -1289; Y. Chiba, N. Kohri, K. Iseki and K. Miyazaki, Improvement of dissolution and bioavailability for mebendazole, an agent for human echinococcosis, by preparing solid dispersion with polyethylene glycol, Chem. Pharm. Bull. 39 (1991 Therefore, poorly soluble drugs may exhibit low bioavailability due to the low absorption rate of the drug through the gastrointestinal membrane due to the low solubility of the drug.

In order to improve the solubility of poorly soluble drugs, studies using solid dispersions have been attempted. (MS Kislalioglu, MA Khan, C. Blount, RW Goettsch and S. Bolton, Physical characterization and dissolution properties of ibuprofen: Eudragit coprecipitates, J. Pharm. Sci. 80 (1991), pp. 799-804; G. Van den Mooter, M. Wuyts, N. Blaton, R. Busson, P. Grobet, P. Augustijns and R. Kinget, Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25, Eur. J. Pharm. Sci. 12 (2001) , pp. 261-269). Solid dispersions are systems in which drug particles are dispersed in a matrix in a solid state, which can significantly increase the surface area of drug particles by significantly reducing the particle size of the drug. In addition, the physical state of the drug particles in the solid dispersion may exist in a crystalline form (partially or entirely in an amorphous form). Therefore, the use of a solid dispersion can significantly improve the solubility of poorly soluble drugs.

As a conventional technique for improving the solubility of coenzyme Q, US Patent No. 7,030,102 discloses a method of improving the solubility of coenzyme Q using a complex with a cyclodextrin, but the effect of improving solubility is extremely weak. International Patent No. 95/05164 and U.S. Patent No. 5,785,976 disclose a technique using a colloid, but have problems such as poor solubility improvement effect or precipitation during storage. Techniques using solid dispersions include U.S. Patent No. 20040014817 for oral use comprising 5 to 35% ubiquinone, 30 to 90% melt processing excipients, 2 to 25% surfactant and other pharmaceutical excipients. Solid dispersion formulations are presented. Although polyvinylpyrrolidone is disclosed as the most preferred carrier, it is possible to increase the solubility of the drug to approximately 200 μg / ml, but there is still room for solubility improvement and amorphous drug due to recrystallization of the drug during the post-preservation period. There is a problem such as that the physical stability of the may be low. The molding temperature for preparing the formulations described above is also described as a relatively high temperature of 80 to 100 ^° C. However, prolonged exposure of the drug to such high molding temperatures may cause drug degradation.

Accordingly, the present inventors have focused on improving the solubility of coenzyme Q and inhibiting the recrystallization of amorphous drug in the solid dispersion, thereby improving physical stability of the amorphous drug. Solid dispersion compositions and methods for their preparation have been found that have significantly improved solubility and improved the physical stability of amorphous drugs in solid dispersions.

Accordingly, an object of the present invention is to improve the solubility of coenzyme Q used as an active ingredient to increase the bioavailability of the drug and to inhibit the recrystallization of the amorphous drug which is thermodynamically unstable in the solid dispersion during the shelf life, solubility of the drug It is to provide a solid dispersion composition and a method for producing the same that can prevent the phenomenon of decreasing.

The present invention relates to a solid dispersion composition and a method for preparing the same, which can improve the solubility of coenzyme Q and improve the physical stability of the amorphous drug in the solid dispersion.

Hereinafter, the present invention will be described in detail.

Coenzyme Q used as an active ingredient includes a combination of 1 to 12 mono-unsaturated trans-isoprenoid units to a benzoquinone backbone. Preferably it is coenzyme Q10 to which 8 to 10, more preferably 10 isoprenoids are bound. Another active ingredient includes ubiquinol formed by reduction of ubiquinone. At this time, the content of coenzyme Q is 1 to 40% by weight, preferably 3 to 30% by weight, more preferably 5 to 20% by weight in the dried composition. If the content of coenzyme Q is less than 1% by weight, the coenzyme Q content may be reduced due to the increased dose of the solid dispersion composition, which may be burdensome for the patient to prepare in the usual dosage. At or above, the dissolution rate of coenzyme Q may be lowered because the ratio of drug in the crystalline state is higher than the drug in the amorphous state in the solid dispersion composition.

Solid dispersion carriers are known as poloxamers and polyoxyethylene-poly is represented by the general formula of HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H Oxypropylene copolymer (polyoxyethylene-polyoxypropylene copolymer) is used. Table 1 shows the various poloxamers that are presented and commonly used in the US Pharmacopoeia. Preferred of these are poloxamers 188, 237, 338 and 407 and most preferred are poloxamer 407. At this time, the content of the polyoxyethylene-polyoxypropylene copolymer is 10 to 90% by weight, more preferably 30 to 60% by weight in the dried composition. When the content of the polyoxyethylene-polyoxypropylene copolymer is 10 wt% or less, it is difficult to expect high solubility of coenzyme Q because the ratio of the crystalline drug is higher than the amorphous drug in the solid dispersion composition. Solubility enhancement is difficult to expect, and the patient's compliance may be reduced because the dose of the entire solid dispersion composition is increased and the burden is on the patient.

Poloxamer shape a b Average molecular weight 124 Liquid 12 20 2090-2360 188 solid 80 27 7680-9510 237 S solid 64 37 6840-8830 338 solid 141 44 12700-17400 407 solid 101 56 9840-14600

In addition, the present invention may use an additive such as a recrystallization inhibitor or an adsorbent to suppress the recrystallization of the amorphous drug that is thermodynamically unstable in the solid dispersion during the storage period. At this time, the additives that can be used include all recrystallization inhibitors or adsorbents that are commercially allowed for human use, and it is preferable to use at least one additive selected from silica derivatives. More preferably, colloidal silicone dioxide is used. Colloidal silicon dioxide has a particle size of 7-16 nm and a specific surface area of 200-400 m ² / g. Various colloidal silicon dioxides are sold under various trade names, and Table 2 shows products sold under the trade name Aerosil. The most desirable of these is the Aerosil 200. The content of the additive of the recrystallization inhibitor or the adsorbent used is 10 to 80% by weight, more preferably 35 to 65% by weight in the formulation. When the amount of the additive is less than 10% by weight, the drug recrystallization inhibitory effect is weak, and over 80% by weight of the excessive adsorption may reduce the solubility of the drug.

Product Name Specific surface area (m ² / g) Density (g / cm ³ ) 130 130 ± 25 0.05 130vs 130 ± 25 0.12 200 200 ± 25 0.05 200vs 200 ± 25 0.12 300 300 ± 30 0.05 380 380 ± 30 0.05

The solid dispersion composition production method may be a melting method or a solvent method. However, the method for preparing a solid dispersion composition is not limited to the above two methods. The melting method is prepared by heating to a temperature higher than the melting point of the active ingredient, more preferably the melting point of the poloxamer. The active ingredient, poloxamer and colloidal silicon dioxide are sufficiently mixed and then melted by heating. When the melting method is used, the preparation temperature may be heated above the temperature at which the active ingredient can be melted, but is preferably kept at 80 ^° C. or lower, and more preferably at 70 ^° C. or lower. Above 80 ^o C can cause problems with the thermal stability of coenzyme Q. When using the solvent method, a method such as vacuum drying, spray drying, heat drying, natural drying or lyophilization may be used to dry the composition solution. At this time, in the case of heat drying, the drying temperature is preferably maintained at 80 ^° C. or lower, and more preferably 70 ^° C. or lower. Above 80 ^o C can cause problems with the thermal stability of coenzyme Q. The solvent method is a method in which the active ingredient, the polyoxyethylene-polyoxypropylene copolymer and colloidal silicon dioxide are dissolved and then dried. As the solvent, a volatile organic solvent can be used. As the organic solvent, aliphatic alcohols such as methanol, ethanol and isopropanol may be used, and more preferably carbon dichloride. Carbon dichloride can not only dissolve the active ingredient, but also poloxamer, and gel the colloidal silicon dioxide, and when used in a sufficient amount, it looks like a solution. In the present invention, the active ingredient, polyoxyethylene-polyoxypropylene copolymer and other additives are dissolved or dispersed in an organic solvent, more preferably in carbon dichloride, and then dried at a temperature of 20 to 80 degrees Celsius to obtain a final product.

The final product produced by the melting method or the solvent method is obtained as a powder with excellent flowability and they can be made into tablets or capsules.

According to the present invention, the solid dispersion of coenzyme Q, which is designed to have excellent solubility and physical stability by containing coenzyme Q as an active ingredient and containing polyoxyethylene-polyoxypropylene copolymer and silica derivative as carrier components of the solid dispersion. Can be provided. Coenzyme Q is used to treat antioxidants and cardiovascular disease, but its bioavailability is low because of its low solubility. Therefore, the present invention is expected to improve the low bioavailability by significantly improving the solubility of coenzyme Q.

Hereinafter, the present invention will be described in more detail with reference to the following Examples, which are not intended to limit the present invention.

Example 1

To prepare a solid dispersion by melting, 8.3 wt% of coenzyme Q10, 41.7 wt% of poloxamer 407, and 50 wt% of colloidal silicon dioxide were mixed. The mixture is heated at 70 degrees Celsius for 30 minutes and then cooled to room temperature to grind to prepare a coenzyme Q10 solid dispersion. X-ray diffraction analysis and differential thermal scanning thermal analysis of the prepared solid dispersion showed that the coenzyme Q10 was mostly amorphous.

[Example 2]

16 mg of coenzyme Q10, 120 mg of poloxamer 407 and 75 mg of colloidal silicon dioxide were added to 1.9 ml of carbon dichloride and dissolved using ultrasonic waves to form a clear yellow gel. This was dried in a vacuum oven at 25 degrees Celsius and then ground to prepare a coenzyme Q10 solid dispersion.

Comparative Example 1

A complex of coenzyme Q10 and cyclodextrin was prepared according to US Pat. No. 7,030,102.

Comparative Example 2

Coenzyme Q10 and polyvinylpyrrolidone solid dispersion were prepared according to US Patent Publication No. 2004/0014817.

Experimental Example 1

The solubility of the coenzyme Q10 solid dispersion prepared in Examples 1 and 2 was compared with Comparative Examples 1 and 2. Coenzyme Q10 was quantified by high-performance liquid chromatograph method by diluting each sample with distilled water to 1 mg / ml with coenzyme Q10 for 48 hours at 37 degrees Celsius. The results were as follows.

sample Solubility (µg / mL) Example 1 807.7 ± 21.7 Example 2 898.6 ± 12.0 Comparative Example 1 1.54 ± 0.12 Comparative Example 2 202.8 ± 22.7 Commercial item 333.6 ± 37.0

As can be seen from the results, it can be seen that Examples 1 and 2 according to the present invention show superior solubility compared to Comparative Examples 1 and 2 and commercially available products.

Claims (11)

At least one component selected from coenzyme Q and its derivatives as an active ingredient, polyoxyethylene-polyoxypropylene copolymer poloxamer 407 as a carrier of the solid dispersion, colloidal silicon dioxide recrystallization inhibitor (recrystallization inhibitor) Or a solid dispersion composition containing the adsorbent. The solid dispersion composition of claim 1, wherein coenzyme Q is coenzyme Q10. The solid dispersion composition of claim 1, wherein the coenzyme Q derivative is ubiquinol produced by reduction of ubiquinone. The solid dispersion composition according to any one of claims 1 to 3, wherein the content of coenzyme Q is 1 to 40% by weight of the total weight of the solid dispersion composition. delete delete delete delete  The solid dispersion composition according to claim 1, wherein the content of the colloidal silicon dioxide is 35 to 65% by weight of the total weight of the solid dispersion composition. Coenzyme Q or its derivatives, poloxamer 407 and colloidal silicon dioxide is sufficiently mixed and melted at a temperature of 60 to 80 degrees Celsius, and then cooled again to room temperature to prepare a solid dispersion containing coenzyme Q Way. delete