LIQUID CRYSTALLINE STRUCTURE-FORMING OMEGA-3-FATTY ACID COMPOSITION

Abstract

The present invention relates to a liquid crystalline structure-forming omega-3-fatty acid composition and, more specifically, provides an omega-3-fatty acid composition comprising: amphoteric lipids which form liquid crystalline structures when exposed to aqueous media such as gastrointestinal juice; omega-3 fatty acids or derivatives thereof; and a liquid crystalline structure-forming aid. The omega-3-fatty acid composition forms self-assembled lyotropic liquid crystals which are thermodynamically stable in structure, irrespective of digestion in the gastrointestinal tract, thereby promoting the solubilization and absorption rate of omega-3-fatty acids as well as providing preparations 30% or more smaller in size than conventional soft gel capsules of omega-3-fatty acid preparations. Thus, the composition can be taken with more ease by geriatric patients and the like and allows for provision of omega-3-fatty acid preparations increasing in in-vivo dissolution and absorption.

Claims

1. An omega-3-fatty acid composition comprising: a liquid crystal former comprising two or more amphoteric lipids containing a nonpolar tail group having 14 to 20 carbon atoms (C.sub.14 to C.sub.20) and a polar head group having a hydroxyl (—OH) or carboxyl group (—COOH); omega-3-fatty acids or derivatives thereof; and a liquid crystalline structure-forming aid of a lipid component, wherein the omega-3-fatty acid composition forms liquid crystals in an aqueous medium.

2. The omega-3-fatty acid composition of claim 1, wherein the omega-3-fatty acid composition includes, based on 100 parts by weight of the composition, 20 to 60 parts by weight of the liquid crystal former, and 40 to 80 parts by weight of the omega-3-fatty acids or derivatives thereof.

3. The omega-3-fatty acid composition of claim 2, wherein the omega-3-fatty acid composition has a weight ratio of the liquid crystal former and the liquid crystalline structure-forming aid of 10:1 to 2:8.

4. The omega-3-fatty acid composition of claim 1, wherein the amphoteric lipids are one or a combination of two or more selected from the group consisting of neutral acyl/diacyl glycerol, phytantriol, and phospholipids.

5. The omega-3-fatty acid composition of claim 4, wherein the neutral acyl/diacyl glycerol is one or a combination of two or more selected from the group consisting of glyceryl monooleate, glyceryl monolinoleate, glyceryl palmitate, glyceryl dioleate, glyceryl dipalmitate, glyceryl phytanoate, glyceryl palmitoleate, glyceryl distearate, glyceryl dielaidiate, and glyceryl dilinoleate.

6. The omega-3-fatty acid composition of claim 1, wherein the liquid crystalline structure-forming aid is one or a combination of two or more selected from the group consisting of phospholipids, unsaturated fatty acids, tocopherol acetate, cholesterols, and vegetable oils.

7. The omega-3-fatty acid composition of claim 6, wherein the phospholipids are one or a combination of two or more selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, phosphatidylinositol, phosphatidic acid, and sphingomyelin.

8. The omega-3-fatty acid composition of claim 6, wherein the unsaturated fatty acids are one or a combination of two or more selected from the group consisting of oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, and 11-eicosenoic acid.

9. The omega-3-fatty acid composition of claim 1, wherein the omega-3-fatty acids are selected from eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA).

10. The omega-3-fatty acid composition of claim 1, wherein the derivatives thereof are selected from the group consisting of ethyl esters, triglycerides, free fatty acids, and phospholipids of omega-3-fatty acids.

11. The omega-3-fatty acid composition of claim 1, further comprising: one or more antioxidants selected from the group consisting of α-tocopherol acetate, butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT).

12. The omega-3-fatty acid composition of claim 1, wherein the composition spontaneously forms lyotropic liquid crystal structures in a gastrointestinal tract.

13. An omega-3-fatty acid oral preparation comprising the omega-3-fatty acid composition of claim 1 and a pharmaceutically acceptable carrier.

14. An omega-3-fatty acid soft capsule comprising the omega-3-fatty acid composition of claim 1 and a pharmaceutically acceptable carrier.

15. The soft capsule of claim 14, wherein the soft capsule is filled with 150 to 1500 mg of the omega-3-fatty acid composition.

Description

DESCRIPTION OF DRAWINGS

[0015] FIG. 1 illustrates dissolution test results of in-vitro EPA ethyl esters of compositions of Examples 6, 8, and 68 and Comparative Examples 1 and 2.

[0016] FIG. 2 illustrates dissolution test results of in-vitro DHA ethyl esters of compositions of Examples 6, 8, and 68 and Comparative Examples 1 and 2.

[0017] FIG. 3 illustrates a result of measuring particle sizes of liquid crystals when the compositions of Examples 6, 8, and 68 are dispersed in an in-vitro condition of in-vivo gastrointestinal tract.

[0018] FIG. 4 illustrates a result of confirming isotropic as a polarization microscope analysis result of liquid crystals having a cubic structure formed when the compositions of Examples 6, 8, and 68 are dispersed in an in-vitro condition of in-vivo gastrointestinal tract.

BEST MODE OF THE INVENTION

[0019] Hereinafter, the present invention will be described in detail.

[0020] The present inventors have conducted various studies to develop a composition containing omega-3-fatty acids with improved dosage compliance of patients by increasing the absorption rate, reducing a dosage, and reducing the size of the preparation, found that a liquid crystal system including amphoteric lipids capable of spontaneously forming (self-assembly) lyotropic liquid crystal structures in the gastrointestinal tract was formulated with omega-3-fatty acids or derivatives thereof to have higher absorption rate than conventional preparations of omega-3-fatty acids, and then completed the present invention.

[0021] Therefore, the present invention provides an omega-3-fatty acid composition including a liquid crystal former comprising two or more amphoteric lipids containing a nonpolar tail group having 14 to 20 carbon atoms (C.sub.14 to C.sub.20) and a polar head group having a hydroxyl (—OH) or carboxyl group (—COOH); omega-3-fatty acids or derivatives thereof; and a liquid crystalline structure-forming aid of a lipid component, wherein the omega-3-fatty acid composition forms liquid crystals in an aqueous medium.

[0022] The omega-3-fatty acid composition may include, based on 100 parts by weight of the composition, 20 to 60 parts by weight of the liquid crystal former, and 40 to 80 parts by weight of the omega-3-fatty acids or derivatives thereof.

[0023] In addition, the omega-3-fatty acid composition may have a weight ratio of the liquid crystal former and the liquid crystalline structure-forming aid of 10:1 to 2:8.

[0024] More specifically, the omega-3 fatty acids may include omega-3, omega-3-fatty acids, omega-3 derivatives (ethyl ester derivatives or carboxylic acid derivatives, omega-3 complexes), or DHA, eicosapentaenoic acid (EPA), etc., which are omega-3 internal components, and these omega-3 fatty acids may be included in an amount of 40 parts by weight to 80 parts by weight based on 100 parts by weight of the total composition. When the omega-3 fatty acids are included in an amount of 40 parts by weight or less, the size of the preparation increases or the amount of capsules taken per dose increases, and as a result, it may be difficult for the patient to take. When the omega-3 fatty acids are included in an amount of 80 parts by weight or more, the ratio of the liquid crystal former is insufficient, and thus the liquid crystalline structures in the living body are not well formed, so that the in-vivo dissolution of the omega-3-fatty acids may be lowered and in-vivo absorption may not be improved.

[0025] The liquid crystal former is preferably 20 to 60 parts by weight based on 100 parts by weight of the total composition. When the liquid crystal former is contained in an amount of less than 20 parts by weight, it is not easy to form a liquid crystal structure in the in-vivo condition, and thus, the in-vivo dissolution of omega-3-fatty acids is reduced and thus in-vivo absorption may not be improved. In addition, when the liquid crystal former is contained in an amount of more than 60 parts by weight, the content of the main component, omega-3-fatty acids is lowered, so that the size of the preparation increases and the amount of capsules taken per dose increases, making it difficult for patients to take medication.

[0026] The liquid crystal former of the present invention has a lipid solution form, and means amphoteric lipids spontaneously forming liquid crystal structure particles of 1000 nm or less, preferably 500 nm or less when exposed to an excess of aqueous media including water, gastrointestinal juice, and the like, and a material including the same. The amphoteric lipids include a polar head group and one or two nonpolar tail groups in a molecular structure, and serve to form nanometer-scale liquid crystals in aqueous media to increase the solubility and dissolution of omega-3-fatty acids in an in-vivo condition, thereby playing an important role in increasing in-vivo absorption. As the liquid crystal structures formed in such an environment, a reversed hexagonal phase, a reversed cubic phase, a multi-lamellar vesicle, etc. may be generated, and the properties of the liquid crystalline structures are not limited, and the structures have an advantage of forming a polar region and a nonpolar region to solubilize both a polar material and a nonpolar material.

[0027] More specifically, the amphoteric lipids are amphoteric lipids comprising 1 to 2 nonpolar tail groups having 14 to 20 carbon atoms and at least one polar head group having a hydroxy or carboxyl group, and more preferably, may be one or a combination of two or more selected from the group consisting of neutral acyl/diacyl glycerol, phytantriol, phospholipids, etc, but are not limited thereto.

[0028] The neutral acyl/diacyl glycerol may be one or a combination of two or more selected from the group consisting of glyceryl monooleate, glyceryl monolinoleate, glyceryl palmitate, glyceryl dioleate, glyceryl dipalmitate, glyceryl phytanoate, glyceryl palmitoleate, glyceryl distearate, glyceryl dielaidiate, and glyceryl dilinoleate.

[0029] The liquid crystalline structure-forming aid is a lipid component that helps the liquid crystal former to self-form liquid crystalline structures in an in-vivo condition (e.g., in the gastrointestinal tract). The liquid crystalline structure-forming aid includes materials with good compatibility with omega-3-fatty acids and excellent biocompatibility, and for example, the liquid crystalline structure-forming aid may be one or a combination of two or more selected from the group consisting of phospholipids, unsaturated fatty acids, tocopherol acetate, cholesterols, and vegetable oils, but is not limited thereto.

[0030] The phospholipids include a polar head group and two nonpolar tail groups, and may include various derived or synthetic phospholipids, including phospholipids derived from soybean or egg yolk. Preferably, the phospholipids may be one or a combination of two or more selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, phosphatidylinositol, phosphatidic acid, and sphingomyelin, but is not limited thereto.

[0031] The unsaturated fatty acids are liquid unsaturated fatty acids at room temperature and a bio-derived component having 1 to 3 double bonds and widely present in animals and plants, have excellent biocompatibility, and serve to form lyotropic liquid crystal structures such as a reversed hexagonal phase, a reversed cubic phase, and a multi-lamellar vesicle in the gastrointestinal tract with the amphoteric lipids forming the liquid crystals. Accordingly, it has been confirmed through the present invention that the solubilization and absorption promoting effects of omega-3-fatty acids were increased.

[0032] The liquid unsaturated fatty acids may be one or a combination of two or more selected from the group consisting of oleic acid, linoleic acid, myristoleic acid, palmitoleic acid, and 11-eicosenoic acid, but are not limited thereto.

[0033] The omega-3-fatty acids may be selected from eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), and the derivatives thereof may be selected from the group consisting of ethyl esters, triglycerides, free fatty acids, and phospholipids of omega-3-fatty acids, but are not limited thereto.

[0034] The composition may further include one or more antioxidants selected from the group consisting of α-tocopherol acetate, butylhydroxyanisole (BHA), and butylhydroxytoluene (BHT).

[0035] The composition may spontaneously form lyotropic liquid crystal structures in the gastrointestinal tract.

[0036] In addition, the present invention provides an omega-3-fatty acid oral preparation including the omega-3-fatty acid composition and a pharmaceutically acceptable carrier.

[0037] In addition, the present invention provides an omega-3-fatty acid soft capsule including the omega-3-fatty acid composition and a pharmaceutically acceptable carrier.

[0038] The soft capsule may be filled with 150 to 1500 mg of the omega-3-fatty acid composition, more preferably 600 to 800 mg of the omega-3-fatty acid composition, but is not limited thereto.

MODES FOR THE INVENTION

[0039] Hereinafter, the present invention will be described in detail with reference to Examples for understanding. However, the following Examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following Examples. Examples of the present invention will be provided for more completely explaining the present invention to those skilled in the art.

<Examples 1 to 20> Preparation of Compositions Including Omega-3-Fatty Acid Ethyl Esters

[0040] Examples 1 to 20 containing omega-3-fatty acid ethyl esters (Omega-3>90EE, K.D.Pharma) were prepared according to components and amounts in Table 1 below. Specifically, in a glass vial, omega-3-fatty acid ethyl ester, liquid crystal formers (glyceryl monooleate, glyceryl dioleate, and phytantriol), and liquid crystalline structure-forming aids (phosphatidylcholine, oleic acid, tocopherol acetate, and cholesterol) were added, and then stirred and mixed at room temperature with a magnetic stirrer. The total medium scale was prepared at 20 g per preparation.

TABLE-US-00001 TABLE 1 Examples (Unit: mg) 1 2 3 4 5 6 7 8 9 10 omega-3-fatty acid 320 320 320 600 600 500 500 500 500 500 ethyl ester Glyceryl monooleate 390 129 215 110 75 200 125 240 125 60 Glyceryl dioleate Phytantriol Phosphatidylcholine 40 301 215 40 75 Oleic acid 50 125 115 240 Tocopherol acetate 10 10 Cholesterol 10 Examples (Unit: mg) 11 12 13 14 15 16 17 18 19 20 omega-3-fatty acid 320 500 500 500 600 320 500 500 500 600 ethyl ester Glyceryl monooleate Glyceryl dioleate 355 125 170 125 110 Phytantriol 355 125 170 125 110 Phosphatidylcholine 75 125 75 125 Oleic acid 80 125 40 80 125 40 Tocopherol acetate Cholesterol

<Examples 21 to 40> Preparation of Compositions Including Omega-3-Fatty Acid Triglycerides

[0041] Examples 21 to 40 containing omega-3-fatty acid triglycerides (KD 480320 TG, K.D.Pharma) were prepared according to components and amounts in Table 2 below. Specifically, in a glass vial, omega-3-fatty acid triglyceride, liquid crystal formers (glyceryl monooleate, glyceryl dioleate, and phytantriol), and liquid crystalline structure-forming aids (phosphatidylcholine, oleic acid, tocopherol acetate, and cholesterol) were added, and then stirred and mixed at room temperature with a magnetic stirrer. The total medium scale was prepared at 20 g per preparation.

TABLE-US-00002 TABLE 2 Examples (Unit: mg) 21 22 23 24 25 26 27 28 29 30 Omega-3-fatty acid 320 320 320 600 600 500 500 500 500 500 triglyceride Glyceryl monooleate 390 355 215 110 75 200 125 240 125 125 Glyceryl dioleate Phytantriol Phosphatidylcholine 40 75 215 40 75 Oleic acid 50 125 115 115 Tocopherol acetate 10 10 Cholesterol 10 Examples (Unit: mg) 31 32 33 34 35 36 37 38 39 40 Omega-3-fatty acid 320 500 500 500 600 320 500 500 500 600 triglyceride Glyceryl monooleate Glyceryl dioleate 355 125 170 125 110 Phytantriol 355 125 170 125 110 Phosphatidylcholine 75 125 75 125 Oleic acid 80 125 40 80 125 40 Tocopherol acetate Cholesterol

<Examples 41 to 60> Preparation of Compositions Including Omega-3-Fatty Acid Phospholipids

[0042] Examples 41 to 60 containing omega-3-fatty acid phospholipids (Omega3MPL, CLS technology) were prepared according to components and amounts in Table 3 below. Specifically, in a glass vial, omega-3-fatty acid phospholipids, liquid crystal formers (glyceryl monooleate, glyceryl dioleate, and phytantriol), and liquid crystalline structure-forming aids (phosphatidylcholine, oleic acid, tocopherol acetate, and cholesterol) were added, and then stirred and mixed at room temperature with a magnetic stirrer. The total medium scale was prepared at 20 g per preparation.

TABLE-US-00003 TABLE 3 Examples (Unit: mg) 41 42 43 44 45 46 47 48 49 50 Omega-3-fatty acid 320 320 320 600 600 500 500 500 500 500 phospholipids Glyceryl monooleate 390 355 215 110 75 200 125 240 125 125 Glyceryl dioleate Phytantriol Phosphatidylcholine 40 75 215 40 75 Oleic acid 50 125 115 115 Tocopherol acetate 10 10 Cholesterol 10 Examples (Unit: mg) 51 52 53 54 55 56 57 58 59 60 Omega-3-fatty acid 320 500 500 500 600 320 500 500 500 600 phospholipids Glyceryl monooleate Glyceryl dioleate 355 125 170 125 110 Phytantriol 355 125 170 125 110 Phosphatidylcholine 75 125 75 125 Oleic acid 80 125 40 80 125 40 Tocopherol acetate Cholesterol

<Examples 61 to 70> Preparation of Compositions Including Omega-3-Fatty Acid Ethyl Esters and Antioxidants

[0043] Examples 61 to 70 containing omega-3-fatty acid ethyl esters (Omega-3>90EE, K.D.Pharma) were prepared according to components and amounts in Table 4 below. Specifically, in a glass vial, omega-3-fatty acid ethyl ester, a liquid crystal former (glyceryl monooleate), liquid crystalline structure-forming aids (phosphatidylcholine, and oleic acid), and antioxidants (tocopherol acetate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT)) were added, and then stirred and mixed at room temperature with a magnetic stirrer. The total medium scale was prepared at 20 g per preparation.

TABLE-US-00004 TABLE 4 Examples (Unit: mg) 61 62 63 64 65 66 67 68 69 70 Omega-3-fatty acid 500 500 500 500 500 500 500 500 500 500 ethyl ester Glyceryl monooleate 163 163 163 163 110 110 110 125 125 125 Phosphatidylcholine 82 90 90 90 Oleic acid 82 82 82 45 45 45 120 120 120 Tocopherol acetate 5 5 5 5 Butylhydroxyanisole 5 5 5 (BHA) Butylhydroxytoluene 5 5 5 (BHT)

<Comparative Examples 1 and 2> Omega-3-Fatty Acid Ethyl Ester and Commercial Preparation (Omacor® Soft Capsule)

[0044] In the present invention, Omacor® soft capsule and omega-3-fatty acid ethyl ester [Omega-3>90EE, K.D.Pharma] were used as Comparative Examples 1 and 2, respectively.

<Experimental Example 1> In Vitro Dissolution Tests of Compositions Including Omega-3-Fatty Acids Ethyl Esters

[0045] In order to predict the absorption behavior in the gastrointestinal tract, in vitro dissolution tests for Examples 6, 8, and 68 and Comparative Examples 1 and 2 were performed.

[0046] Specifically, the composition prepared in Example was filled in a hard capsule (No. 00) so as to be 500 mg as omega-3-fatty acids ethyl ester. A test solution (fed state simulated intestinal fluid, FeSSIF) of pH 5.0 containing 15.000 g of Triton X-100, 8.250 g of sodium taurocholic acid, 2.950 g of soybean-derived phosphatidylcholine, 8.650 g of acetic acid, 11.874 g of sodium chloride, and 4.040 g of sodium hydroxide per 1 L of the test solution was prepared, and then dissolution tests and analysis were performed under the following conditions.

[0047] The dissolution tests were carried out in an apparatus (paddle method) of a dissolution test method 2 among general test methods of the Korean Pharmacopoeia. A FeSSIf effluent of pH 5.0 containing 900 mL of 1.5% (w/v) Triton X-100 was maintained at 37.0±0.5° C., and the rotation speed of a paddle was set to 100 rpm. 5 mL of a sample was collected, and the dissolution solution was not separately supplemented after collection. The collected sample was analyzed in a high performance liquid chromatography (HPLC) apparatus, and the analysis conditions were as follows.

[0048] 1. HPLC Analysis Conditions [0049] Column: Column (Aegispak C18-L) filled with octadecyl silylated silica gel for liquid chromatography with a particle diameter of 5 μm in stainless steel tube having a length of 150 mm and an inner diameter of 4.6 mm [0050] Moving phase: Purified water:Acetonitrile=10:90 (v/v) [0051] Wavelength: 215 nm (ultraviolet absorbance spectrophotometer) [0052] Flow rate: 1.0 ml/min [0053] Column temperature: 25° C. [0054] Injection amount: 10 μl

[0055] As a result, as illustrated in FIGS. 1 and 2, it was confirmed that the compositions of Examples 6, 8, and 68 according to the present invention promoted the absorption rate of omega-3-fatty acids in the artificial intestinal fluid as compared with Comparative Examples 1 and 2 which were conventional omega-3-fatty acid preparations, and accordingly, it can be expected that the in-vivo absorption rate will increase.

<Experimental Example 2> Confirmation of Liquid Crystal Structure Particles Containing Omega-3-Fatty Acids

[0056] In order to evaluate whether to spontaneously form lyotropic liquid crystal structures in the gastrointestinal tract, polarized light microscopy and dynamic light scattering particle size analysis for Examples 6, 8, and 68 were used.

[0057] Specifically, a test solution (fed state simulated intestinal fluid, FaSSIF) of pH 5.0 containing 8.250 g of sodium taurocholic acid, 2.950 g of soybean-derived phosphatidylcholine, 8.650 g of acetic acid, 11.874 g of sodium chloride, and 4.040 g of sodium hydroxide per 1 L of purified water, and a test solution (pre-fed state simulated intestinal fluid, FaSSIF) of pH 6.5 containing 1.700 g of sodium taurocholic acid, 0.600 g of soybean-derived phosphatidylcholine, 3.400 g of sodium dihydrogen phosphate, 6.200 g of sodium chloride, and 0.400 g of sodium hydroxide per 1 L of purified water were prepared. The composition prepared in Example was filled into soft capsules so as to be 500 mg as omega-3-fatty acid ethyl ester, and exposed to 900 ml of the simulated intestinal fluid before and after meals under the dissolution test conditions of Experimental Example 1 for 30 minutes, and then polarization microscope and dynamic light scattering particle size analysis were performed under the following conditions.

[0058] As a result, as illustrated in FIGS. 3 and 4, it can be confirmed that the composition of Example according to the present invention forms liquid crystal particles in the simulated intestinal fluid.

<Experimental Example 3> Preparation of Soft Capsules of Composition Containing Omega-3-Fatty Acids

[0059] To prepare soft capsules filled with a composition containing omega-3-fatty acids, soft capsules with various sizes (5 oval, 12 oblong, 14 oval, etc.) were produced after preparing a gelatin film.

[0060] Specifically, a gelatin film containing 415 g of succinic acid gelatin, 130 g of concentrated glycerin, 305 g of purified water, and 150 g of amorphous sorbitol solution per 1 kg of the film was prepared and after 1 day of aging, filled with a composition containing omega-3-fatty acids at a film thickness of 0.080 mm, and then dried for about 2 days under 25° C./blowing conditions, and the soft capsule was produced.

[0061] As described above, specific parts of the present invention have been described in detail, and it will be apparent to those skilled in the art that these specific techniques are merely preferred embodiments, and the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.