KR100956583B1 - A solid dispersion comprising ubidecarenone, method thereof and pharmaceutical composition comprising the solid dispersion - Google Patents

Abstract

The present invention relates to a solid dispersion of ubide carenone, a preparation method thereof, and a pharmaceutical composition comprising a solid dispersion of ubide carenone. The present invention has improved solubility and bioavailability and is easy to handle. Solid preparations of can be obtained.

Uvide carenone, CoQ10, solid dispersion

Description

Solid dispersion of ubide carenone, a method for preparing the same, and a pharmaceutical composition comprising the same

FIG. 1 is data showing the results of dissolution testing of ubidecarenone capsules prepared by the methods of Formulation Examples 1 and 2 and Comparative Examples 1 and 2 using pH 1.2 buffer containing 1% polysorbate 80 as an eluent.

FIG. 2 is a diagram showing a comparison of X-ray powder diffraction data patterns of the ubide carenone solid dispersion prepared by the method of Example 1 and the crystalline ubide carenone raw material.

Figure 3 is a view showing a comparison of the differential scanning calorimetry of the ubide carenone solid dispersion and crystalline ubide carenone raw material prepared by the method of Examples 1 and 2 of the present invention.

Figure 4 shows an optical micrograph of the ubide carenone solid dispersion and the crystalline ubide carenone raw material prepared by the method of Example 1 of the present invention. (a) and (b) are photographs observing the crystalline ubide carenone raw material, (c) and (d) are photographs observing the ubide carrenone solid dispersion prepared by the method of Example 1 of the present invention. .

The present invention relates to a solid dispersion of ubide carenone, a preparation method thereof, and a pharmaceutical composition comprising a solid dispersion of ubide carenone.

Attempts have been made to improve their solubility and absorption in the use of poorly soluble and / or poorly absorbent materials as pharmaceuticals. Amorphization is known as a physicochemical method of such an attempt. The unpurification method is a method of breaking down the crystal structure of a substance and miniaturizing it to the molecular level. A solid dispersion can be mentioned as one form of this unpurification method. The solid dispersion contains a substance dispersed at the molecular level in the solid and is in a state in which the so-called solid is dissolved in the solid. In the solid dispersion, since the dispersed materials do not contact each other, crystallization hardly occurs, and generally, the stability in the amorphous state of the material is improved.

As a method of preparing a solid dispersion, a solvent method (Chem. Pharm. Bull., 34 (8), 3408 (1986)), which dissolves a substance and a water-soluble polymer in a suitable solvent, removes the solvent. Melting method (see J. Pharm. Sci., 59, 937 (1970)), and a mixed grinding method of mixing and grinding a material and a water-soluble polymer in a ball mill or the like (cf. Pharmaceutical, 45 (4), 291 (1985)), and spray drying methods for spray drying a drug and a water-soluble polymer solution (Chem. Pharm. Bull., 44 (3), 568 (1996)).

Representative of poorly soluble drugs is ubide carenone (hereinafter abbreviated as CoQ10). CoQ10 is biochemically located in the myocardial mitochondrial electron transport system and plays an important role in energy production. Clinically, CoQ10 improves congestive symptoms and angina symptoms caused by deterioration of cardiac function such as chronic hypertension, ischemic heart disease, and valve disease. It is a valid substance. In addition, CoQ10 is known to be effective in diseases including muscle relaxation, periodontal disease, drug-induced deficiency correction and immune recovery (AIDS, allergy), and is known to be effective in preventing aging and various diseases due to its powerful antioxidant activity. have. Although CoQ10 is found in fish, meat, etc., it is not enough to meet the needs of food alone, and it decreases gradually in the body as it ages. Therefore, CoQ10 supplements can be used to maintain body vitality and prevent arteriosclerosis. The need for more is increasing.

As such, CoQ10, which is increasing in necessity, has been limited in use due to the characteristics of CoQ10. In other words, CoQ10 is a yellow soluble powder at room temperature having a melting point of 48 to 52 ℃, poor absorption and bioavailability due to its large molecular weight and crystallinity, and is also unstable against light, heat, alkali and low melting point CoQ10 There is a difficulty in formulating.

A method of solubilizing CoQ10 in liquid formulation is disclosed in Korean Patent Application No. 1992-12250, Korean Registered Patent No. 27307, and the like. CoQ10 aqueous solutions prepared by these disclosed methods have a low CoQ10 content, a large amount of surfactant, a liquid phase has a disadvantage in that the stability is difficult and difficult to handle it is difficult to apply to most solid preparations. In addition, Korean Patent Application No. 2005-0084126 discloses a monoester of polyglycerol having an average degree of polymerization of 10 and a C18 fatty acid, or a mono, di, tri, or pentaester of polyglycerol having an average degree of polymerization of 3 to 6 and a fatty acid having 18 carbon atoms. A water-soluble composition containing CoQ10 having an average particle diameter of 110 nm or less using water is disclosed. Since the method disclosed herein uses a homogenizer to make the particle size smaller and homogenous, the particle size becomes larger after elapse of time. There is a problem in stability, and there is a problem in that it is suitable for a liquid formulation having a low content of CoQ10. In order to overcome the problems of the liquid formulation of CoQ10, the study of solubilized powder of CoQ10 has become an alternative.

As a technique for solubilizing powder of CoQ10, U.S. Patent No. 5,989,583 discloses a solid powder production technique containing 10 to 15% of CoQ10 by lyophilization or spray drying using solid lipids, phospholipids, and other sugars. Doing. However, the technique disclosed by the patent is disadvantageous in mass production because the content of CoQ10 is relatively low, and expensive equipment is required for manufacturing by lyophilization and manufacturing costs are increased due to long manufacturing time.

Korean Patent No. 28370 describes a method of dissolving a fat-soluble active vitamin or ubiquinone using hydrogenated lecithin. However, the technique disclosed by this patent requires other solubilizing solubilizers and has problems such as poor solubility and stability.

U.S. Patent Application 2003-0147927 discloses coli in a self-nanoemulsified drug delivery system (SNEDDS) using oils and surfactants and medium chain mono-and diglycerides. Kollidone VA 64, maltodextrin, microcrystalline cellulose and the like were mixed and powdered. However, the technique disclosed by the above patent has a disadvantage in that many other excipients must be used in order to solidify the SNEDDS in the liquid phase, so that the content of CoQ10 is low and there are many handling problems due to the large amount of the liquid excipient.

US Patent Application No. 2005-0142123 discloses a method of granulating together corn starch by spraying a fluidized bed granulator with high pressure homogenization by mixing a warmed and dissolved polysaccharide or gelatin aqueous solution with CoQ10 melt. . However, the method disclosed by the patent reduces the particle size of the emulsion by homogenization under high pressure, so it is time-consuming and has a disadvantage in that the manufacturing method is not simple.

Therefore, the present inventors have solved the above problems and while studying the solid dispersion of CoQ10 which improves the solubility and bioavailability of CoQ10, when the emulsifier and hydrophilic polymer are used together, the dissolution rate and stability are improved and the handling is easy. It has been found that one solid CoQ10 can be produced and the present invention has been completed.

An object of the present invention is to provide a solid dispersion of CoQ10 that can improve the solubility and bioavailability of CoQ10, improve the stability and physical properties of CoQ10, and increase the content of CoQ10 in the solid dispersion.

Still another object of the present invention is to provide a method for preparing the solid dispersion of CoQ10.

Still another object of the present invention is to provide a pharmaceutical composition comprising the solid dispersion of CoQ10.

In one embodiment, the present invention relates to a solid dispersion of CoQ10 comprising CoQ10 and an emulsifier and a hydrophilic polymer.

CoQ10 is a poorly soluble material having a structure of Formula 1 below, and in the specific embodiment of the present invention, crystalline CoQ10 was used.

The emulsifier included in the solid dispersion of the present invention is a substance which improves the dissolution rate of CoQ10, which is a poorly soluble substance, and may be used as long as it is present in solid or semi-solid at room temperature. Specifically, polyglycerol fatty acid esters, sucrose fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, polyethylene glycol fatty acid esters and mixtures of mono-, di- or tri-glycerides, caprylic / ka Mono-, di- or mono / di-glycerides, such as fric acid mono- or di-glycerides, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene fatty acid esters, propylene glycol mono- or di-fatty acid esters Or an organic acid can be used. Preferably polyglycerol fatty acid esters and polyoxyethylene-polyoxypropylene block copolymers can be used, more preferably polyglycerol fatty acid esters, examples of which are decaglycerol monostearate, decaglycerol monooleate And decaglycerol monolinoleate.

The amount of the emulsifier used in the present invention is preferably 0.1 to 20 parts by weight, more preferably 0.2 to 10 parts by weight based on 1 part by weight of the active ingredient CoQ10. When the amount of the emulsifier is less than 0.1 parts by weight, the dissolution of the main component is hardly observed, and when the amount of the emulsifier exceeds 20 parts by weight, it is difficult to prepare a tablet or capsule which is an easy-to-use formulation for use.

The hydrophilic polymer of the present invention is a material used for dispersing CoQ10 and improving stability and physical properties. The hydrophilic polymer is not particularly limited, and any hydrophilic polymer may be used as long as it is pharmaceutically or foodly acceptable. Alkyl celluloses such as, for example, methyl cellulose; Hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; Hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose or hydroxypropyl methylcellulose; Carboxyalkyl alkyl celluloses such as carboxymethyl cellulose; Alkali metal salts of carboxyalkyl cellulose such as sodium carboxyalkyl cellulose; Carboxyalkyl alkyl celluloses such as carboxymethyl ethyl cellulose; Carboxyalkylcellulose esters; Starch; Pectin, such as sodium carboxymethyl amylopectin; Chitin derivatives such as chitosan; Alginic acid, its alkali metal and ammonium salts; Polysaccharides such as carrageenan, galactomannan, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum, dextrin, cyclodextrin (GyD) or maltodextrin; Polyacrylic acid and salts thereof; Polymethacrylic acid and its salts, methacrylate copolymers, aminoalkyl methacrylate copolymers; Polyvinyl acetal diethylamino acetate; Sugar-based surfactants such as sucrose distearate, sucrose monodistearate, sucrose monopalmitate; Polyvinyl alcohol; Polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate; Polyalkylene oxides such as polyethylene oxide and polypropylene oxide; Polyethylene glycol polyvinyl alcohol esters; And copolymers of ethylene oxide and propylene oxide. Preferably, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol polyvinyl alcohol ester, dextrin, cyclodextrin, maltodextrin and the like. These hydrophilic polymers may be used alone or in combination of one or more.

The amount of the hydrophilic polymer used in the present invention may be used in 0.1 to 20 parts by weight, preferably 0.2 to 10 parts by weight based on 1 part by weight of CoQ10.

In the present invention, the physical properties of the solid dispersion are greatly improved when both the emulsifier and the hydrophilic polymer are used, compared to the case of preparing the solid dispersion using only the emulsifier. In addition, in terms of solubility, when the solid dispersion was prepared by using an emulsifier and a hydrophilic polymer together, the physical properties were improved, the particles were smaller, the dispersion was better, and the dissolution rate was excellent. Therefore, by preparing a CoQ10 soluble solid dispersion using a semi-solid or solid emulsifier and a hydrophilic polymer as a carrier of the solid dispersion at room temperature, it is possible to improve the dissolution rate and stability while at the same time easy to handle solid powder.

CoQ10 solid dispersion of the present invention may further comprise an antioxidant. Further included antioxidants reduce the oxidative degradation of CoQ10 and prevent the oxidation of lipids, emulsifiers to improve the stability of the solid dispersion. Examples of additionally included antioxidants include tocopherol and its analogues (eg, tocopherol acetate), butyrate hydroxytoluene, and the like, and the amount of antioxidant included may be used in an amount of 0.0001 to 0.1 parts by weight based on 1 part by weight of CoQ10. Preferably, 0.001 to 0.05 parts by weight may be used.

CoQ10 solid dispersion according to the present invention is added to the inorganic carriers silicon dioxide, talc, hydrotalcite, aluminum magnesium silicate, titanium dioxide, stearic acid, magnesium stearic acid or a mixture thereof to make handling easier and improve fluidity It can be used as, preferably silicon dioxide can be used. The amount of the inorganic carrier further included is 0.001 to 2 parts by weight, preferably 0.01 to 1 part by weight based on 1 part by weight of CoQ10.

In another aspect, the present invention relates to a method for preparing a CoQ10 solid dispersion.

In one specific embodiment, the present invention relates to a method for preparing a solid dispersion of CoQ10 comprising dissolving or dispersing CoQ10 together with an emulsifier and a hydrophilic polymer in a suitable solvent and removing the solvent from the lysate or dispersion. . In the above production method, CoQ10, an emulsifier, and a hydrophilic polymer may be heated in order to dissolve or disperse more easily in a solvent, and the range of heating is 40 to 50 ° C.

As the solvent used to prepare the CoQ10 solid dispersion of the present invention, any solvent that is acceptable to pharmaceuticals and foods that can dissolve or disperse CoQ10, an emulsifier, and a hydrophilic polymer can be used. For example, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, hexane and the like may be used alone or in combination of two or more thereof. Preferably, ethanol, dichloromethane or acetone may be used. If ethanol and dichloromethane or acetone can be used in a ratio of 1 to 2: 1. The solvent amount is preferably 1 to 50 parts by weight, more preferably 5 to 20 parts by weight based on 1 part by weight of the total amount of CoQ10, an emulsifier, a hydrophilic polymer and the like.

In preparing the CoQ10 solid dispersion of the present invention, any method of removing the solvent may be used as long as it is known in the art, and in the specific embodiment of the present invention, the solvent is removed by spray drying in a spray dryer or a fluidized bed granulator. .

As another specific embodiment, the step of homogeneously melting the CoQ10 and the emulsifier and the hydrophilic polymer by heating to a temperature of 200 to 240 ℃; It relates to a method of producing a solid dispersion of CoQ10 comprising the step of rapidly cooling and pulverizing the molten mixture.

The solid dispersion of CoQ10 prepared according to the present invention has very excellent dissolution characteristics and stability, and is easy to manufacture and can be produced in large quantities, and has excellent oral absorption with high absorption efficiency in vivo.

In another aspect, the present invention is to provide a pharmaceutical composition of ubide carenone comprising the CoQ10 solid dispersion.

The solid dispersion of the present invention can be used as a medicine as it is, it is usually preferable to prepare and administer a preparation in the form of fine granules, granules, tablets, capsules, dry syrup. For example, the preparation of the solid dispersion may be carried out through a conventional formulation process such as mixing process, assembly process, formulation process, tableting process, coating process, capsule filling process, etc. In addition, a pharmaceutical composition may be prepared, if necessary, by using an appropriate preparation additive, and the prepared pharmaceutical composition may be prepared as a preparation of the above form.

As additives for the preparation, for example, excipients (e.g. lactose, mannitol, crystalline cellulose, corn starch, potato starch, etc.), disintegrants (e.g. carboxymethyl starch sodium, carboxymethyl cellulose calcium, croscarmellose sodium, poly) Vinyl polypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, etc., flow improvers (e.g., hard silicic anhydride, hydrous silicon dioxide, etc.), colorants (e.g., titanium oxide, yellow trioxide, etc.), seasoning agents (e.g., Tartaric acid, ascorbic acid, citric acid, etc.), surfactants (e.g., sodium lauryl sulfate, polysorbate 80, polyoxyethylene hardened castor oil, etc.), dispersants (e.g., crystalline cellulose, carboxyvinyl polymer, etc.), lubricants (e.g., Magnesium stearate, etc.), and the usage-amount of the additive for these preparations can be suitably selected by those skilled in the art. These additives for preparations may be added in one or two or more steps as appropriate, for example, may be added during the preparation of the solid dispersion, or may be added in the step of preparing the preparation from the solid dispersion.

The invention will be explained in more detail through the following examples. These examples are presented by way of example only, so that the present invention may be more understood, these examples should not limit the scope of the invention.

Example  One: CoQ10  Contains 33.3% Solid dispersion  Produce

After dissolving 500 g of ethanol at 40 to 50 ° C. while stirring 20 g (33.3%) of decaglycerin monostearate, 18.74 g (31.2%) of hydroxypropylmethylcellulose was slowly dispersed. To this solution, a solution of 20 g (33.3%) of CoQ10 dissolved in 500 ml of dichloromethane was mixed, followed by 0.06 g (0.1%) of DL-a-tocopheryl acetate and 1.2 g of silicon dioxide (2). %) Was added and mixed homogeneously. 48.5 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Co., Ltd.). Spray conditions are as follows.

Inlet temp .: 80 ℃, Outlet temp .: 48 ~ 53 ℃, Atomizer speed (disc type): 10,000 rpm, Flow rate (peristaltic pump): 4.0

Example  2: CoQ10  25% containing Solid dispersion  Produce

After dissolving 800 ml of ethanol at 40 to 50 ° C. while stirring 20 g (25.0%) of decaglycerin monostearate, 38.32 g (47.9%) of hydroxypropylmethylcellulose was slowly dispersed. In this solution, a solution of 20 g (25.0%) of CoQ10 dissolved in 800 ml of dichloromethane was mixed, followed by adding 0.08 g (0.1%) of DL-a-tocopheryl acetate and 1.6 g (2%) of silicon dioxide. Mixed. 62.7 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Kim).

Example  3: CoQ10  Contains 33.3% Solid dispersion  Produce

After dissolving 500 g of ethanol at 40 to 50 ° C. while stirring 20 g (33.3%) of decaglycerin monostearate, 18.74 g (31.2%) of hydroxypropylmethylcellulose was slowly dispersed. After mixing 20 g (33.3%) of CoQ10 in 500 ml of acetone, 0.06 g (0.1%) of DL-a-tocopheryl acetate and 1.2 g (2%) of silicon dioxide were added and mixed homogeneously. . 48.5 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Co., Ltd.).

Example  4: CoQ10  25% containing Solid dispersion  Produce

After dissolving 800 ml of ethanol at 40 to 50 ° C. while stirring 20 g (25.0%) of decaglycerin monostearate, 38.32 g (47.9%) of hydroxypropylmethylcellulose was slowly dispersed. After mixing 20 g (25.0%) of CoQ10 in 800 ml of acetone, add 0.08 g (0.1%) of DL-a-tocopheryl acetate and 1.6 g (2%) of silicon dioxide, and mix homogeneously. . 62.7 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Kim).

Example  5: CoQ10  Contains 33.3% Solid dispersion  Produce

20 g (33.3%) of CoQ10, 20 g (33.3%) of decaglycerin monostearate and 18.74 g (31.2%) of hydroxypropylmethylcellulose were heated and melted at 200 to 240 ° C. with stirring to form a uniform melt, followed by rapid melting on ice water. To cool. After cooling sufficiently, it was pulverized appropriately and appled with a No. 60 sieve to prepare 54.2 g of a solid dispersion.

Example  6: CoQ10  25% containing Solid dispersion  Produce

20 g (25.0%) of CoQ10, 20 g (25.0%) of decaglycerin monostearate, and 38.32 g (47.9%) of hydroxypropylmethylcellulose were heated and melted at 200 to 240 ° C. with stirring to form a uniform melt, followed by rapid melting on ice water. To cool. After cooling sufficiently, it was ground appropriately and appled with a No. 60 sieve to prepare 72.6 g of a solid dispersion.

Example  7: CoQ10  Contains 33.3% Solid dispersion  Produce

After dissolving 500 ml of ethanol at 40 to 50 ° C. while stirring 20 g (33.3%) of decaglycerol monooleate, 18.74 g (31.2%) of hydroxypropylmethylcellulose was slowly dispersed. To this solution, a solution of 20 g (33.3%) of CoQ10 dissolved in 500 ml of dichloromethane was mixed and added with 0.06 g (0.1%) of DL-a-tocopheryl acetate and 1.2 g (2%) of silicon dioxide. Mixed. 48.5 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Co., Ltd.).

Example  8: CoQ10  25% containing Solid dispersion  Produce

After dissolving 800 ml of ethanol at 40 to 50 ° C., 20 g (25.0%) of decaglycerol monooleate was dissolved with stirring, and 38.32 g (47.9%) of hydroxypropylmethylcellulose was slowly dispersed. In this solution, a solution of 20 g (25.0%) of CoQ10 dissolved in 800 ml of dichloromethane was mixed, followed by adding 0.08 g (0.1%) of DL-a-tocopheryl acetate and 1.6 g (2%) of silicon dioxide. Mixed. 62.7 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Kim).

Example  9: CoQ10  Contains 33.3% Solid dispersion  Produce

20 g (33.3%) of CoQ10, 20 g (33.3%) of decaglycerin monooleate and 18.74 g (31.2%) of hydroxypropylmethylcellulose were heated and melted with stirring at 200 to 240 ° C to form a homogeneous melt, which was then rapidly cooled on ice water. To cool. After cooling sufficiently, it was pulverized suitably and appled with a No. 60 sieve to prepare 53.7 g of a solid dispersion.

Example  10: CoQ10  25% containing Solid dispersion  Produce

20 g (25.0%) of CoQ10, 20 g (25.0%) of decaglycerin monooleate, and 38.32 g (47.9%) of hydroxypropylmethylcellulose were heated and melted at 200 to 240 ° C. with stirring to form a uniform melt, followed by rapid melting on ice water. To cool. After cooling sufficiently, it was ground appropriately and appled with a No. 60 sieve to prepare 71.5 g of a solid dispersion.

Example  11: CoQ10  Contains 33.3% Solid dispersion  Produce

After slowly dispersing 18.74 g (31.2%) of hydroxypropylmethylcellulose in 500 ml of ethanol, 20 g (33.3%) of poloxamer 407 was added thereto and dissolved at room temperature. To this solution, a solution of 20 g (33.3%) of CoQ10 dissolved in 500 ml of dichloromethane was mixed and added with 0.06 g (0.1%) of DL-a-tocopheryl acetate and 1.2 g (2%) of silicon dioxide. Mixed. The mixed solution of 48.5g of a solid dispersion was prepared using a spray dryer (N-D101, Dongjin Kim).

Example  12: CoQ10  25% containing Solid dispersion  Produce

After slowly dispersing 38.32 g (47.9%) of hydroxypropylmethylcellulose in 800 ml of ethanol, 20 g (25.0%) of poloxamer 407 was added thereto and dissolved at room temperature. In this solution, a solution of 20 g (25.0%) of CoQ10 dissolved in 800 ml of dichloromethane was mixed, followed by adding 0.08 g (0.1%) of DL-a-tocopheryl acetate and 1.6 g (2%) of silicon dioxide. Mixed. 62.7 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Co., Ltd.).

Example  13: CoQ10  Contains 33.3% Solid dispersion  Produce

20 g (33.3%) of CoQ10, 20 g (33.3%) of poloxamer 407 and 18.74 g (31.2%) of hydroxypropylmethylcellulose were heated and melted with stirring at 200 to 240 ° C to form a uniform melt, followed by rapid cooling on ice water. I was. After cooling sufficiently, it was ground appropriately and appled with a No. 60 sieve to prepare 53.2 g of a solid dispersion.

Example  14: CoQ10  25% containing Solid dispersion  Produce

20 g (25.0%) of CoQ10 and 20 g (25.0%) of poloxamer 407 and 38.32 g (47.9%) of hydroxypropylmethylcellulose were heated and melted with stirring at 200 to 240 ° C. to form a uniform melt, which was then rapidly heated on ice water. Cooled. After cooling sufficiently, it was ground appropriately and appled with a No. 60 sieve to prepare 72.4 g of a solid dispersion.

Example  15: CoQ10  Contains 33.3% Solid dispersion  Produce

After dissolving 500 ml of ethanol at 40 to 50 ° C. with stirring 20 g (33.3%) of decaglycerin monostearate, 9.37 g (15.6%) of povidone K-30 and 9.37 g (15.6%) of hydroxypropylmethylcellulose were dissolved. Disperse slowly. To this solution, a solution of 20 g (33.3%) of CoQ10 dissolved in 500 ml of dichloromethane was mixed and added with 0.06 g (0.1%) of DL-a-tocopheryl acetate and 1.2 g (2%) of silicon dioxide. Mixed. 48.5 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Co., Ltd.).

Example  16: CoQ10  25% containing Solid dispersion  Produce

After dissolving 800 ml of ethanol at 40 to 50 DEG C while stirring 20 g (25.0%) of decaglycerin monostearate, 19.16 g (23.95%) of povidone K-30 and 19.16 g (23.95%) of hydroxypropylmethylcellulose were dissolved. Disperse slowly. In this solution, a solution of 20 g (25.0%) of CoQ10 dissolved in 800 ml of dichloromethane was mixed, followed by adding 0.08 g (0.1%) of DL-a-tocopheryl acetate and 1.6 g (2%) of silicon dioxide. Mixed. 62.7 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Kim).

Example  17: CoQ10  Contains 33.3% Solid dispersion  Produce

20 g (33.3%) of CoQ10, 20 g (33.3%) of decaglycerin monostearate, 9.37 g (15.6%) of povidone K-30 and 9.37 g (15.6%) of hydroxypropylmethylcellulose were heated with stirring at 200 to 240 ° C, Melting gave a uniform melt and then cooled rapidly on ice water. After cooling sufficiently, it was pulverized suitably and appled with a No. 60 sieve to prepare 52.5 g of a solid dispersion.

Example  18: CoQ10  25% containing Solid dispersion  Produce

20 g (25.0%) of CoQ10, 20 g (25.0%) of decaglycerin monostearate, 19.16 g (23.95%) of povidone K-30 and 19.16 g (23.95%) of hydroxypropylmethylcellulose are heated with stirring at 200 to 240 ° C, Melting gave a uniform melt and then cooled rapidly on ice water. After cooling sufficiently, it was ground appropriately and appled with a No. 60 sieve to prepare 71.6 g of a solid dispersion.

Example  19: CoQ10  Contains 33.3% Solid dispersion  Produce

After slowly dispersing 18.74 g (31.2%) of hydroxypropylmethylcellulose in 500 ml of ethanol, 20 g (33.3%) of sucrose fatty acid ester (HLB = 12) was added thereto and dissolved. To this solution, a solution of 20 g (33.3%) of CoQ10 dissolved in 500 ml of dichloromethane was mixed and added with 0.06 g (0.1%) of DL-a-tocopheryl acetate and 1.2 g (2%) of silicon dioxide. Mixed. 48.5 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Co., Ltd.).

Example  20: CoQ10  25% containing Solid dispersion  Produce

38.32 g (47.9%) of hydroxypropylmethylcellulose was slowly dispersed in 800 ml of ethanol, and 20 g (25.0%) of sucrose fatty acid ester (HLB = 12) was added thereto to dissolve. In this solution, a solution of 20 g (25.0%) of CoQ10 dissolved in 800 ml of dichloromethane was mixed, followed by adding 0.08 g (0.1%) of DL-a-tocopheryl acetate and 1.6 g (2%) of silicon dioxide. Mixed. 62.7 g of a solid dispersion was prepared using the spray liquid (N-D101, Dongjin Kim).

Formulation example  One: CoQ10 Solid dispersion  Hard Capsule  Produce

A solid dispersion containing 33.3% of CoQ10 prepared in Example 1 was mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as an excipient, and the granule mixture weight of 500 mg corresponding to 50 mg of CoQ10 per capsule was measured. Hard capsules were filled according to the preparation method of the capsule section of the Pharmacopoeia General Regulations.

Formulation example  2: CoQ10 Solid dispersion  Hard Capsule  Produce

The solid dispersion containing 25.0% of CoQ10 prepared in Example 2 was mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as an excipient, and the granule mixture weight of 500 mg corresponding to 50 mg of CoQ10 per capsule was measured. Hard capsules were filled according to the preparation method of the capsule section of the Pharmacopoeia General Regulations.

Formulation example  3: CoQ10 Solid dispersion  Hard Capsule  Produce

The solid dispersion containing 33.3% of CoQ10 prepared in Example 3 was mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as an excipient, and the granule mixture weight of 500 mg corresponding to 50 mg of CoQ10 per capsule was measured. Hard capsules were filled according to the preparation method of the capsule section of the Pharmacopoeia General Regulations.

Formulation example  4: CoQ10 Solid dispersion  Hard Capsule  Produce

The solid dispersion containing 25.0% of CoQ10 prepared in Example 4 was mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as an excipient, and the granule mixture weight of 500 mg corresponding to 50 mg of CoQ10 per capsule was measured. Hard capsules were filled according to the preparation method of the capsule section of the Pharmacopoeia General Regulations.

Comparative example  One: CoQ10 Drug substance  Hard Capsule  Produce

A method of preparing a capsule term in the Korean Pharmaceutical Regulations, containing 500 mg of CoQ10 per capsule by mixing CoQ10 (manufactured by Daewoong Chemical) with a mixture of lactose and corn starch (product name: Starlac, Roquette) as an excipient. Filled into hard capsules according to.

Comparative example  2: CoQ10 Solubilization  Raw material( Ultrasome - CoQ10 Hard with) Capsule  Produce

Pharmacopharmaceutical formulation of 500mg of CoQ10 per capsule, which is mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as an excipient with CoQ10 solubilizing ingredients (product name: Ultrasome-CoQ10, Herbamed). In the general rule, the hard capsules were filled according to the preparation method of the capsule.

Experimental Example  1: Dissolution test

The general pharmaceutical test using a hard capsule containing CoQ10 solid dispersion of Formulation Examples 1 and 2 and 500 ml of pH 1.2 buffer containing 1% polysorbate 80 (Tween80, Sigma) as test solutions. According to Method 2, the dissolution test was performed at 50 rpm, and the eluate was taken at 15, 30, 60, and 120 minutes after the start of the test, and analyzed by HPLC. At this time, HPLC method was analyzed under the following conditions.

Dissolution Test Equipment: Vankel VK-7020S

Eluent: 500 mL pH 1.2 buffer with 1% Tween 80

Eluent Temperature: 37.0 ± 0.5 ℃

Rotational Speed: 50 rpm

Assay: HPLC method

Detector: Ultraviolet absorption photometer (wavelength 275nm)

Column: Capcell Pak C18 (4.6 × 150mm, 5um)

Column temperature: 40 ℃

Mobile phase: Mixed anhydrous ethanol and methanol (70:30)

Flow rate: 1.0 mL / min

The result is shown in FIG. 1. As can be seen in Figure 1, the hard capsules of Formulation Examples 1 and 2 showed a higher dissolution rate than the hard capsules of Comparative Examples 1 and 2, CoQ10 solubility according to the present invention than CoQ10 raw material and commercially available CoQ10 solubilizing raw material It was found that the solid dispersion was a much improved formulation.

Experimental Example  2: X-ray Diffraction spectroscopy  analysis

The crystallinity of the solid dispersion prepared according to Example 1 and the crystalline CoQ10 were compared and evaluated using an X-ray diffractometer (Mac Science, Japan, Model: M18XHF-SRA). Figure 2 shows the X-ray powder diffraction pattern (XRD spectrum data) of the CoQ10 solid dispersion and crystalline CoQ10 prepared according to Example 1, this data is 40 kV using an X-ray powder diffractometer Data measured with a CuK-α beam under a voltage of and a current of 300 mA. Unlike the crystalline CoQ10, the patterns of FIG. 2 show that the solid dispersions are amorphous due to the very low diffraction angle and relative intensity of the diffraction peaks.

Experimental Example  3: differential scanning calorimeter ( DSC ) analysis

Using a differential scanning calorimetry (Mettler-Toledo, DSC822e), the crystallinity of the solid dispersion prepared according to Example 1 alc 2 and CoQ10 raw material was compared and evaluated. FIG. 3 shows a chart of differential scanning calorimetry of CoQ10 solid dispersion and crystalline CoQ10 prepared according to Examples 1 and 2, and this data was obtained at 25 ° C. using a sealable aluminum pan and lid. Data measured while heating at a temperature of 10 ° C / min per minute with a heating ramp up to 120 ° C. Referring to the pattern of FIG. 3, unlike crystalline CoQ10, the solid dispersions had a small or no enthalpy value, which is believed to result in a "reduced molecular order" due to a reduction in the amount of heat required to dissolve the crystallized molecular population. The same low melting point or disappearance on DSC.

Experimental Example  4: micrograph analysis

Using the optical microscope (OLYMPUS, BX 51), the properties of the solid dispersion prepared according to Example 1 and CoQ10 raw material was compared and evaluated. Figure 4 shows a photograph of the CoQ10 solid dispersion prepared in Example 1 (Fig. 4 (c) and (d)) and the crystalline CoQ10 (Fig. 4 (a) and (b)) under a microscope This data is magnified at 200x and 500x magnification. Referring to FIG. 4, unlike the crystalline CoQ10, the solid dispersions were amorphous because they showed a rounded shape in which the crystalline form disappeared.

Soluble solid dispersion of CoQ10 according to the present invention can increase the solubility to improve the bioabsorption and bioavailability, it is possible to efficiently mass production by the production method of the present invention. In addition, it is possible to provide a solid dispersion of CoQ10 which is very suitable for the manufacture of medicines, foods, cosmetics materials and the like compared to conventional CoQ10 raw materials and has excellent stability and ease of handling.

Claims (22)

Including CoQ10 and emulsifiers and hydrophilic polymers, The content of CoQ10 is at least 25% by weight, Hydrophilic polymers include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol polyvinyl alcohol esters, dextrin, cyclodextrin At least one selected from the group consisting of (CyD), maltodextrin, and mixtures thereof, Solid dispersion of CoQ10. The solid dispersion of claim 1, further comprising an antioxidant or an inorganic carrier. The solid dispersion of claim 1, wherein the emulsifier is semisolid or solid at room temperature. The mixture of claim 3 wherein the emulsifier is a polyglycerin fatty acid ester, sucrose fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, sorbitan fatty acid ester, polyethylene glycol fatty acid ester and a mixture of mono-, di- or tri-glycerides, Mono-, di- or mono / di-glycerides, such as caprylic / capric acid mono- or di-glycerides, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene fatty acid esters, propylene glycol mono- Or a di-fatty acid ester, or a solid dispersion. The solid dispersion according to claim 4, wherein the emulsifier is a polyglycerin fatty acid ester or a polyoxyethylene-polyoxypropylene block copolymer. The solid dispersion of claim 1, wherein the emulsifier is included in an amount of 0.2 to 10 parts by weight based on 1 part by weight of CoQ10. delete The solid dispersion according to claim 1, wherein the hydrophilic polymer is 0.2 to 10 parts by weight based on 1 part by weight of CoQ10. The solid dispersion of claim 2, wherein the antioxidant is tocopherol or an analog thereof or butylate hydroxytoluene. The solid dispersion of claim 2, wherein the antioxidant is included in an amount of 0.0001 to 0.1 parts by weight based on 1 part by weight of CoQ10. The solid dispersion according to claim 2, wherein the inorganic carrier is silicon dioxide, talc, hydrotalcite, aluminum magnesium silicate, titanium dioxide, stearic acid, magnesium stearic acid or mixtures thereof. The solid dispersion according to claim 2, wherein the inorganic carrier is 0.001 to 2 parts by weight based on 1 part by weight of CoQ10. (A) dissolving or dispersing CoQ10, an emulsifier and a hydrophilic polymer together in one or two or more mixed solvents selected from the group consisting of methanol, ethanol, isopropyl alcohol, dichloromethane, acetone and hexane, and (B) Removing the solvent from the lysate or dispersion, The content of CoQ10 is at least 25% by weight, Hydrophilic polymers include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol polyvinyl alcohol esters, dextrin, cyclodextrin At least one selected from the group consisting of (CyD), maltodextrin, and mixtures thereof, Method for preparing a solid dispersion of CoQ10. The method of claim 13, wherein the removing of the solvent of step (B) is by spray drying. The method of claim 13, further comprising dissolving or dispersing the antioxidant or emulsifier in step (A). The method of claim 13 comprising dissolving or dispersing while warming to 40-50 ° C. in step (A). (A) homogeneously melting the CoQ10 and the emulsifier and the hydrophilic polymer to a temperature of 200 to 240 ℃; And (B) rapidly cooling and pulverizing the molten mixture, The content of CoQ10 is at least 25% by weight, Hydrophilic polymers include hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol polyvinyl alcohol esters, dextrin, cyclodextrin At least one selected from the group consisting of (CyD), maltodextrin, and mixtures thereof, Method for preparing a solid dispersion of CoQ10. A pharmaceutical composition of ubide carenone comprising the CoQ10 solid dispersion of claim 1. A pharmaceutical composition of ubide carenone comprising the CoQ10 solid dispersion of claim 2. delete delete delete

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