KR20100043318A - Composition for the self-emulsifying nanoemulsion containing hydrogenated cocoglyceride - Google Patents

Abstract

PURPOSE: A self-emulsifying nanemulsion composition containing coenzyme Q10 having high solubility is provided to improve solubility in solution of water-insoluble coenzyme Q10 and bioavailability. CONSTITUTION: A self-emulsifying nanoemulsion of insoluble drug contains hydrogenated cocoglyceride as a solubilizer of insoluble active ingredient. The insoluble active ingredient is coenzyme Q10. The content of the insoluble active ingredient is 0.5-40 weight%. The content of the hydrogenated cocoglyceride is 5-40 weight%. The composition additionally contains emulsifying agent having 9-17 hydrophilic lipophilic balance. The composition additionally contains cosurfactant having 1-8 of hydrophilic lipophilic balance.

Description

Composition for the self-emulsifying nanoemulsion containing hydrogenated cocoglyceride}

The present invention relates to a method and a composition for preparing a self-emulsifying nanoemulsion using a hydrogenated coco-glyceride as a dissolving agent of an active ingredient and an emulsifier, wherein the active ingredient is coenzyme Q10 (coenzyme). It relates to a self-emulsifying nanoemulsion composition of a poorly soluble drug which is poorly soluble in water but has a high solubility of 20 mg / mL or more in hydrogenated coco-glycerides as in Q10). The present invention can improve bioavailability by improving solubility in aqueous solutions of poorly soluble drugs in water, such as coenzyme Q10.

Coenzyme Q10, 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 as an antioxidant and 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 lowered and lowered. Bioavailability is shown. Because the drug must be dissolved before it can be absorbed through the biofilm. Drugs that do not dissolve are very difficult to pass through the biofilm. 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. Similarly, in the case of transdermal absorption, undissolved drugs are not absorbed through the skin.

Therefore, several conventional techniques for improving the solubility of poorly soluble drugs such as coenzyme Q10 have been proposed. U.S. Patent Publication No. 20040014817 discloses an oral solid dispersion formulation consisting of 5 to 35% ubiquinone, 30 to 90% melt processing excipients, 2 to 25% surfactant and other pharmaceutical excipients. However, although the solubility of the drug can be increased to approximately 200 μg / ml with the above manufacturing techniques, there is still room for improvement of the solubility and the physical stability of the amorphous drug due to the drug recrystallization during the post-preparation shelf life is low. there was. The molding temperature for preparing the formulations described above is also described as a relatively high temperature of 80 to 100 ^° C. However, such high molding temperatures are undesirable because they may affect the stability of the drug.

US Patent No. 7030102 discloses a composition in which a complex is formed between coenzyme Q10 and cyclodextrin. However, when the formulation was prepared using coenzyme Q10 and betacyclodextrin as measured in the present invention, the solubility was measured to be lower than 2 μg / ml. Therefore, it is not suitable for use as a preparation for improving the solubility of coenzyme Q10 to improve the bioavailability of the drug.

US Patent Publication No. 20030147927 discloses a self-emulsifying drug delivery system consisting of Cremophor ^® , Capmul ^® , lemon oil and coenzyme Q10. However, even if the formulation is prepared as described in the present invention, it is not easy to prepare the nanoemulsion and there is a problem in that there is a lack of a specific method for preparing the nanoemulsion.

In US Patent Publication No. 20050147659, an oil-in-water (O / W / O type) emulsion was prepared to provide a composition adsorbed on a microporous inorganic material or a swellable polymer in water. However, the preparation of the formulation using this technique can lead to an increase in manufacturing cost due to the complicated manufacturing process, and the dissolution of the drug can be delayed or suppressed by the binding to the inorganic substance.

WO 9856368 shows a formulation in which coenzyme Q10 is dissolved in coconut oil and enclosed in gelatin capsules. However, simply dissolving in vegetable oil to increase the solubility is difficult to expect good absorption because it is not emulsified well even when administered in the body, and the ability to emulsify oil for each person is difficult to expect evenly effective.

Korean Patent No. 10-0553160 proposes a nano-sized phospholipid liposome composition comprising coenzyme Q10 for the purpose of inhibiting skin aging. However, when the formulation is prepared using this technique, the content of coenzyme Q10 is relatively low, such as 0.01 to 0.5% by weight, and the method of preparing the liposome composition is complicated and the stability of the liposome is poor.

In Korean Patent No. 10-0712823, in order to improve the bioavailability of coenzyme Q10, a nanoemulsion concentrate containing coenzyme Q10, a dissolving agent, a surfactant, an oil, a pH adjuster, and an antioxidant was prepared and encapsulated in a soft capsule. . However, when the formulation is prepared using this technique, the additive content excluding coenzyme Q10 in the formulation is high, so that the dosage of the entire nanoemulsion composition is increased when the coenzyme Q10 is prepared in the usual dosage, which is burdensome for the patient to take. This can reduce patient compliance.

Therefore, the present inventors have concentrated on a way to improve the solubility of poorly soluble drugs by preparing a self-emulsifying nanoemulsion formulation, unlike the prior art using hydrogenated coco-glycerides as a dissolving agent of poorly soluble drugs The method of preparing an emulsion was found and it was found that dissolving the active ingredient having a solubility of 20 mg / mL or more in hydrogenated coco-glyceride and then making the nanoemulsion according to the present invention can greatly improve the solubility of the active ingredient.

Accordingly, an object of the present invention is to improve the solubility of active ingredients having a solubility of 20 mg / mL or more in hydrogenated coco-glycerides such as coenzyme Q10 using a self-emulsifying nanoemulsion containing hydrogenated coco-glycerides. It is to provide a self-emulsifying nanoemulsion composition that can increase the transdermal bioavailability.

The present invention provides a self-emulsifying agent capable of improving the solubility in an aqueous solution of an active ingredient having a solubility of 20 mg / mL or more in hydrogenated coco-glycerides, such as coenzyme Q10, using a self-emulsifying nanoemulsion containing hydrogenated coco-glycerides. It relates to a type nanoemulsion composition.

Hereinafter, the present invention will be described in detail.

Hydrogenated coco-glycerides are used as solubilizers to dissolve active ingredients such as coenzyme Q10. The content of the solubilizer contains 5 to 40% by weight, more preferably 7 to 25% by weight of the total weight of the composition. If the content of the solubilizer is less than 5% by weight, it is difficult to fully dissolve the active ingredient, so it is difficult to expect sufficient solubility of the active ingredient.If the content of the solvent is more than 40% by weight, the active ingredient and the solvent mixture may be diluted in water. When the nano-sized particles are difficult to form, solubility of the active ingredient may decrease.

Coenzyme Q10 used as an active ingredient comprises a terpenoid side chain portion of the basic structure of coenzyme Q consisting of 1 to 12 mono-unsaturated trans-isoprenoid units. . At this time, the content of the active ingredient exhibiting high solubility of at least 20 mg / mL in coenzyme Q10 and hydrogenated coco-glyceride is 0.5 to 40% by weight of the total weight of the composition, more preferably 5 to 30% by weight. If the content of the active ingredient is more than 40% by weight, it is difficult to expect further solubility improvement because the drug is not completely dissolved in the stock solution. In the case of oral administration, if the active ingredient is less than 0.5% by weight, the dose of the whole nanoemulsion solution is increased when the active ingredient is prepared in the usual dose, which may reduce the patient's compliance. Not desirable Here, the content of the active ingredient is 0.5 or less depending on the dilution ratio after diluting the nanoemulsion stock with a solvent such as water, ethanol, or a pharmaceutically usable excipient for oral administration in liquid form or transdermal administration in ointment, cream, gel form. It is obvious that the weight can be lowered to below% by weight. Examples thereof include drinks prepared by mixing the self-emulsifying nanoemulsion with water, and external preparations such as cosmetics prepared by diluting with an appropriate solvent and adjusting the viscosity.

As an emulsifying agent for preparing the nanoemulsion stock solution, it is preferable to use a conventional emulsifier having a hydrophilic lipophilic balance of 9 to 17. More preferably, Macrogol 15 hydroxystearate sold under the trade name Solutol HS 15, Polyoxyl 35 castor oil sold under the trade name Cremophor ELP, and Cremophor RH40 traded. PEG40 hydrogenated castor oil, polyoxyethylene sorbitan (Tween 20, 40, 60, 80), glyceryl ester sold under the trade names Imwitor 375 and 380, Brij 30 (POE (4) lauryl ether), Brij 35 (polyethylene glycol dodecyl ether), and one or more emulsifiers selected from the group consisting of saturated polyglycolized C8-C10 glycerides sold under the brand names Labrasol. The content of the emulsifier is to contain 10 to 90% by weight, more preferably 30 to 60% by weight of the total weight of the composition. If the content of the emulsifier is 10% by weight or less, it is difficult to prepare a nano-sized emulsion when diluted in water, and the emulsifier does not sufficiently emulsify the dissolving agent and thus cannot exhibit its original effect. At 90% by weight or more, the content of the coenzyme Q10 in the nanoemulsion stock solution is decreased, and when the oral solution is to be administered orally, the dose is increased at the usual dose, which may be a burden for the patient to reduce compliance.

Co-surfactants can disperse nanoemulsions easily and uniformly, as well as assist in stabilization to provide compositional uniformity. As the cosurfactant for preparing the nanoemulsion composition of the present invention, a conventional surfactant having a hydrophilic lipophilic equilibrium value of 1 to 8 can be used. More preferably ethoxydiglycol sold under the trade name Transcutol, propylene glycol laurate sold under the trade name Lauroglycol FCC, oleyl macrogol sold under the trade name Labrafil M 1944 CS or M2125CS. 6 glycerides (Macrogol-6 glycerides), glyceryl monocaprylate sold under the name Capmul MCM C8, glyceryl mono and dicaprate sold under the name MCM C10, One or more cosurfactants selected from the group consisting of glyceryl monostearate, glycerol fatty acid esters sold under the trade name Gelucire, and Sorbitan monostearate can be used. The cosurfactant is one containing 30% by weight or less, more preferably 15% by weight or less of the total weight of the composition. If the content of the co-surfactant is 30% by weight or more, emulsification by the emulsifier does not occur, rather it may lower the absorption of the formulation. In addition, when the content of the active ingredient is prepared in the usual dosage, the dose of the nanoemulsion stock solution is increased, which may be a burden for the patient to reduce the compliance of the patient.

In addition, when ethanol, propylene glycol or polyethylene glycol is added to the nanoemulsion stock solution, the semi-crosslinked stock solution can be liquefied more rapidly in the body.

The method of preparing the nanoemulsion stock solution may use a melting method or a solvent method. However, the method for preparing the nanoemulsion stock solution is not limited to the above two methods. When using the melting method, the production temperature is preferably kept at 80 ^° C. or lower, more preferably at 60 ^° C. or lower. In the active component, 80 ^o C or higher can cause some problems in heat stability, and it is heated to 80 ^o C over all the active ingredients and solvents above 80 ^o C due to the presence in the molten state is meaningless. The molten nanoemulsion composition is stored at room temperature to prepare a liquefied or semi-solidified nanoemulsion composition. The solvent method is a method of preparing drugs and additives by dissolving them in an organic solvent such as ethanol.

The nanoemulsion stock solution prepared as described above may be used on its own without mixing with other ingredients. The nanoemulsion composition may be diluted with water or a pharmaceutically usable excipient and used as a tablet, capsule, powder, liquid, ointment, cream, or tonic. It can also be used as a dosage form. When the nanoemulsion composition is liquid at room temperature, the nanoemulsion composition may be filled into a capsule or adsorbed into an appropriate adsorbent, and then prepared into a tablet, a capsule, or a powder. If the nanoemulsion stock solution is semisolid at room temperature, it can be used by filling it into capsules and can be made into tablets or powders with some adsorbents. In addition, the nanoemulsion composition may be used as a beverage after dilution with water, and the nanoemulsion composition may be prepared as an external preparation or cosmetic by adding water or an oil component and adjusting the viscosity as appropriate.

The present invention relates to a method and a composition for preparing a self-emulsifying nanoemulsion using a hydrogenated coco-glyceride as a dissolving agent of an active ingredient and an emulsifier, wherein the active ingredient is coenzyme Q10 (coenzyme). Provided is a self-emulsifying nanoemulsion composition of poorly soluble drug, which is poorly soluble in water but has a high solubility of at least 20 mg / mL in hydrogenated coco-glycerides as in Q10). The present invention can improve bioavailability by improving solubility in aqueous solutions of poorly soluble drugs in water, such as coenzyme Q10.

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

Example 1

To 100 mg of coenzyme Q10, a uniform mixture of 100 mg of hydrogenated coco-glyceride (Witepsol H35) and 400 mg of macrogol 15 hydroxystearate (Solutol H15) was added at 40 ° C. and uniformly stirred on a stirrer using a magnetic bar to prepare a nanoemulsion stock solution. Get

Example 2

933 mg of water was added to Example 1 to obtain a yellow oil-in-water emulsified coenzyme Q10-containing composition when mixed in a general manner. At this time, the average emulsified particle diameter of the emulsified particle of coenzyme Q10 was about 100 nm.

Example 3

To prepare 100 mg of coenzyme Q10, 3.2 g of hydrogenated coco-glyceride (Witepsol H35), 1.5 g of macrogol 15 hydroxystearate (Solutol H15) and 700 mg of propylene glycol laurate (Lauroglycol FCC) were prepared to prepare a nanoemulsion stock solution. Oil gel was prepared by adding 350 mg of sodium alginate.

Example 4

To 100 mg of coenzyme Q10, add a homogeneous mixture consisting of 70 mg of hydrogenated coco-glycerides (Witepsol H35), 400 mg of macrogol 15 hydroxystearate (Solutol H15), and 200 mg of propylene glycol laurate (Lauroglycol FCC). Stock solutions were prepared.

Example 5

930 mg of water was added to Example 4 to obtain a yellow oil-in-water emulsion type coenzyme Q10-containing composition. At this time, the average emulsified particle diameter of the emulsified particle of coenzyme Q10 was about 35 nm.

Example 6

100 mg of coenzyme Q10 was dissolved in 100 mg of hydrogen cocoglyceride (Witepsol H35) at 40 ° C., and 400 mg of polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40) was added thereto, followed by well stirring to prepare a nanoemulsion stock solution.

Example 7

100 mg of coenzyme Q10 was dissolved in 100 mg of hydrogen cocoglyceride (Witepsol H35) at 40 ° C., and 400 mg of polyoxyethylene sorbitan monooleate (Tween 80) was added thereto, followed by stirring well to prepare a nanoemulsion stock solution.

Example 8

100 mg of pure ethanol was added to Example 1 to obtain a yellow oil-in-water emulsified coenzyme Q10-containing composition. At this time, the composition before adding water was semisolid at room temperature, but at 37 ° C., it was changed to a transparent emulsion within a few seconds.

[Comparative Example]

Comparative Example 1

A composition was prepared containing 10 mg of coenzyme Q10 according to the method disclosed in U.S. Patent No. 0147927, and the solubility in water of the compositions and Examples 1, 4, and 6, respectively, was measured in pH 6.8 phosphate buffer solution. In the case of Patent No. 0147927, the solubility was 3 mg / mL, but in Examples 1, 4 and 6, the solubility was 8 mg / mL or more.

Experimental Example

In order to evaluate the pharmacokinetic behavior of coenzyme Q10 in the body, Example 4, a commercial product and a coenzyme Q10 powder were administered to Sprague-Dawley Rats. 30 mg / kg or equivalent was administered orally to each experimental rat. The powder was suspended in 5% PEG / 95% MC (0.5%) and the commercial product and Example 4 were administered as it was developed without further dilution. Test drug was orally administered to each experimental rat (Male Sprague-Dawley rats 270-300g) at the prescribed dose, and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24 hr. It was. Blood samples were centrifuged at 4500 rpm for 5 minutes to separate plasma and stored frozen until analysis. Plasma samples were quantified by HPLC to measure the blood concentration of the drug over time. The pharmacokinetic properties of the drugs were evaluated using the WinNonlin program based on the obtained blood concentration results.

Experiment result

Drug concentration-time curves in plasma obtained after administration of the test substance to each experimental animal are shown in FIG. 1 and pharmacokinetic parameters are shown in Table 1. In conclusion, it can be seen that Example 4 according to the present invention is much superior to the powder, and AUC is 2-4 times higher and Cmax value is 2-5 times higher than the soft capsules of domestic D company. It can be seen that the utilization rate increases significantly.

 Pharmacokinetic Parameters (Mean ± Standard Deviation) of CoQ10 after Oral Administration in Rats Tmax (hr) Cmax (ng / mL) AUC0-24 (ng * hr / mL) Cmax (ng / mL) AUC0-24 (ng * hr / mL) R.B. (%) Powder 12 ± 7.6 86.6 ± 57.8 1110 ± 774 2.89 ± 1.93 37.1 ± 25.8 100 Example 4 6.0 ± 2.1 480 ± 347 5070 ± 2770 15.4 ± 11.2 * 162 ± 90.1 * 438 Commercial item 8.6 ± 4.7 235 ± 81.1 3190 ± 832 6.69 ± 2.18 90.9 ± 23.3 245

* p <0.05, statistical significance compared to powder

RB: relative bioavailability compared to powder.

Figure 1 shows the drug concentration-time curve in plasma according to the present invention.

Claims (12)

 A self-emulsifying nanoemulsion composition of a poorly soluble drug containing hydrogenated coco-glycerides as a dissolving agent of poorly soluble active ingredient. 2. The self-emulsifying nanoemulsion composition of poorly soluble drug according to claim 1, wherein the poorly soluble active ingredient is a substance having a solubility of 20 mg / mL or more in hydrogenated coco-glycerides. The self-emulsifying nanoemulsion composition of the poorly soluble drug according to claim 1, wherein the poorly soluble active ingredient is coenzyme Q10. The self-emulsifying nanoemulsion composition of the poorly soluble drug according to any one of claims 1 to 3, wherein the content of the poorly soluble active ingredient is 0.5 to 40% by weight of the total weight of the composition. . The self-emulsifying nanoemulsion composition of poorly soluble drug according to any one of claims 1 to 3, wherein the content of the hydrogenated coco-glyceride as a solubilizer is 5 to 40% by weight of the total weight of the composition. The self-emulsifying nanoemulsion composition of the poorly soluble drug according to any one of claims 1 to 3, wherein an emulsifier having a hydrophilic lipophilic balance of 9 to 17 is further added. 7. The emulsifier according to claim 6, wherein the emulsifier is Macrogol 15 hydroxystearate, Polyoxyl 35 castor oil, Polyethylene glycol 40 hydrogenated castor oil, Polyoxyethylene sorbent Tween 20, 40, 60, 80, glyceryl ester, polyoxyethylene 4 lauryl ether, polyethylene glycol dodecyl ether, saturated polyglycolide C8-C10 glyceride (Saturated polyglycolized C8-C10 glyceride) A self-emulsifying nanoemulsion composition of poorly soluble drug, characterized in that at least one selected from. The self-emulsifying nanoemulsion composition of the poorly soluble drug, characterized in that the content of the emulsifier is 10 to 90% by weight of the total weight of the composition. 7. The self-emulsifying nanoemulsion composition of poorly soluble drug according to claim 6, further comprising a co-surfactant having a hydrophilic lipophilic balance of 1 to 8. 10. The co-surfactant of claim 9, wherein the co-surfactant is ethoxydiglycol, propylene glycol laurate, oleoyl macrogol 6 glycerides, glyceryl mono Selected from glyceryl monocaprylate, glyceryl mono and dicaprate, glyceryl monostearate, glycerol fatty acid esters, sorbitan monostearate (span 60) Self-emulsifying nanoemulsion composition of poorly soluble drug, characterized in that at least one. 10. The self-emulsifying nanoemulsion composition of poorly soluble drug according to claim 9, wherein the content of the cosurfactant is 1 to 30% by weight of the total weight of the composition.  10. The self-emulsifying nanoemulsion of poorly soluble drug according to claim 6 or 9, wherein the ethanol, propylene glycol (PG) or polyethylene glycol (PEG) contains 1% to 30% by weight of the total weight of the composition. Composition.

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