KR100818091B1 - Pharmaceutical oral composition containing flavonolignans using auto micellization drug delivery system - Google Patents

Abstract

   The present invention relates to a flavonolignan-containing pharmaceutical composition exhibiting excellent therapeutic effect by significantly enhancing the oral bioavailability by increasing the solubility and dissolution rate of the flavonolignan component of poor absorption.

  Flavonolignan, bioavailability, composition

Description

   Pharmaceutical oral composition containing flavonolignans using auto micellization drug delivery system}

   Figure 1 is a graph showing the rate and amount of drug eluted from the formulation under acidic conditions in the gastrointestinal tract.

   FIG. 2 is a graph showing the rate and amount of drug eluting from the agent under alkaline conditions, particularly in the small intestine and large intestine.

   3 is a graph showing the concentration of the drug in plasma over time showing the comparative oral bioavailability with the reference drug and the soft capsule of Example 1.

The present invention relates to a pharmaceutical composition of oral flavonolignan using an automatic micelle drug delivery system, in more detail, the present invention relates to an extract of Cardus marianus which is a flavonolignan component as an active ingredient, It relates to an oral composition consisting of at least one active ingredient selected from purified silybin or derivatives thereof, curcuma extract, curcumin purified therefrom and derivatives thereof, and a surfactant and a cosolvent.

   Flavonoids are aromatic polyphenolic compounds that are widely distributed in all plants and are present in all areas of the plant, including leaves, stems, fruits, roots, seeds and flowers. Plants exist as glycosides, substances in the form of sugars.

   Flavonoids are known to have antibacterial, anticarcinogenic, antiviral, anti-allergic and anti-inflammatory activity. Flavonoids, in particular, have stronger antioxidant properties than vitamins C, E, and selenium.

   The cells and tissues that make up our bodies are exposed to free radicals and free radicals that are produced during normal oxygen metabolism and toxins in the environment. Many types of flavonoids can capture and neutralize free radicals present in tissues in our body, and some flavonoids are superoxide dismutase (SOD) and glutathione peroxidase (GOD), which are antioxidant enzymes in the body. Can regulate activity. It can also adsorb to metal ions, thereby inhibiting these metals, which act as catalysts to increase the production of free radicals.

   There have been many studies on flavonoid content and its component analysis in important plants both at home and abroad, and also the use of these substances to control cardiovascular diseases through the inhibition of anticancer, antioxidant, antiviral, and cholesterol, and to control diseases causing diseases in humans. The utility of this is being studied.

   There is a growing interest in the development and use of flavonoids as they are known to inhibit the oxidation of the organism that causes disease.

   Prior to the 1990s, technologies related to extracts, such as ginkgo biloba, have already been known for the mainstream. Since 1990, not only ginkgo biloba, but also extracts of plants, such as green tea, persimmon leaves, pine needles, green beans, and buckwheat, are easily found in medicine. The technologies to be utilized have been developed, and the fields of application are expanding to odor removal, skin cosmetics, health drinks, and health foods.

   Since the mid-1990s, the field of plant extracts has been expanded, and in the medical field, as new flavonoids are extracted, various diseases to be treated are treated, such as liver disease, diabetes, rheumatoid arthritis, various cancers, analgesics, viral diseases, and allergic diseases. It has been found that there is pharmacological activity in vascular diseases such as arteriosclerosis, myocardial diseases, stress, and depression.

   It is recognized that the flavonoid material has the effect of preventing and treating diseases in vivo, and new flavonoid materials are continuously developed every year.

Patent application trends related to flavonoids are as follows, in particular, the development of a liver disease treatment, and the like is actively progressing.

Application by domestic and foreign countries   Name of representative invention Domestic Foreign 1978-1980 One One  Extraction and purification of flavonoid compounds from ginkgo biloba (80-1397) 1981-1985 One 0  Method for preparing a high concentration of silvinine extract from seeds of Cardus marianus (85-4141) 1986-1987 0 2  Extraction and Purification of Flavonoid Compounds (87-2530) 1990 8 4  Extraction and Purification of Active Substances Effective for Vascular Circulatory Disorders (90-7390) 1992 7 3  Anti-inflammatory, Anti-allergic, and Antirheumatic Agents of Bifuranoids Obtained from Human Honey (92-11752) 1993 2 3  Production Method of Flavonoid Anticancer Substances by Culture of Agar Fructus Root (93-27270) 1995 7 4  Mugwort extract for the treatment of gastrointestinal diseases (95-21957) Facial cleansing composition containing mung bean flavonoids (95-37612) 1996 29 0  Antistress composition (96-8230), safflower extract and blood circulation improving agent containing the same (96-39952) 1998 65 20  Composition for preventing and treating liver disease containing hesperindine (98-10888), composition for preventing and treating atherosclerosis containing naringin or naringenin (98-11450) 1999 30 17  Asthma treatment containing phosphorus extracts (99-2009), food composition for health promotion containing ginseng and citrus skin-derived substances (99-20441)

   Among these flavonoids and their derivatives, in particular, flavonolignan components such as silymarin are generally insoluble in water or poorly soluble, and thus have a low bioavailability when applied orally, which makes it difficult to obtain a desired therapeutic effect. .

   Particularly in the flavono league, silymarin is an extract of thistle (Silybum marianum) and has been applied to liver hepatobiliary diseases for hundreds of years. 1989), a flavonolignan component widely used for the treatment of Amamnita phalloides poisoning (Hurby 1983).

   Silymarin contains four structural isomers of silybinin (Silibinin = SBN), isosililibin (Isosilibinin = ISBN), silycristin (Silicristin = SCN) and silidinin (Silidianin = SDN). Silibinin is known to be a flavonolignan component that has a major medicinal effect.

Figure 1.Chemical structural formulas of silymarin flavonoids

   In addition to antioxidant activity, silymarin inhibits Kupffer cells, prevents fibrosis of liver, and also has anti-inflammatory effects. Toxic substances in liver cell membranes bind to these receptors and interfere with the destruction of cell membranes, thereby stabilizing liver membranes. Protect.

   In particular, the main component of Silybum marianum (Silybum marianum or Cardus marianus) is not solubility in water, so the absorption rate after oral administration is very low and the bioavailability is about 20-40%. Because of this low bioavailability, it is inconvenient to administer 140 mg (60 mg of silybin) two or three times a day with silymarin, the recommended oral dose when liver function is lowered. intravenously with disodium dihemisucccinate).

In pharmacokinetics, the peak blood concentration reaching time is 1.7-2.2 hours, and peak blood concentration and oral bioavailability are proportional to dose. Only about 1-2% is excreted through urine and the rest is excreted in bile. The average body remaining time is about 5.5 hours and the half-loss period is about 4 hours.

The present invention relates to a pharmaceutical composition that significantly enhances the oral bioavailability of the silymarin preparation among the flavonolignan components.

   The existing patent on the dissolving method of silybin (published No. 1996-013361) is a method of making an aqueous solution of silymarin, which is dissolved in a polyethylene glycol and ethanol mixed solution and then added to an aqueous solution of polysorbate. In particular, the surfactant is an aqueous solution containing about 7.5 times and 10 times the weight of the silymarin as the absolute dose of the surfactant is too large, in view of the characteristics of the soy medicine to be taken for a long time there are problems such as toxicity and rejection of taking.

   Another patent, Korean Patent Publication No. 1996-0028916 prepared an aqueous alcohol solution and suspended flavonolignan in this solution, and then heated the solution to obtain a clear solution, which was then concentrated again to form a mixed precipitate, which was then filtered under vacuum conditions. It is a method of drying under a very complicated manufacturing process, which requires special evaporation, concentration, and drying equipment, causing expensive manufacturing costs, and there is a concern for mixing residual solvents. In addition, solubility and bioavailability has a disadvantage that is significantly lower than the present invention. This method is patented by Germany's Madaus Company and is commercialized and marketed in Korea.

In addition, recently disclosed Korean Patent Publication No. 2001-0008804 relates to an oral microemulsion composition consisting of a surfactant, an organic solvent which is a co-surfactant, and an oil, using Kardus Marianus extract as an active ingredient. This patent uses relatively high amounts of dimethyl isosorbide as a component weight ratio of 31 w / w% as a co-surfactant in the formulations of the examples commonly used for comparative evaluation of bioavailability. Dimethyl isosorbide, used as a co-surfactant, is commercially available under the trade name Arlasolve, and a typical pharmaceutical use is used as a transdermal absorption accelerator, and is mainly used in cosmetics such as external ointments and lotions. It is an organic solvent. In particular, the half lethal dose (LD ₅₀ ) is dimethylisosorbide 5.63 mg / kg (rat, oral), Cremopoa RH 40 16 g / kg (rat, oral), glycofurol 3.5 mg / kg ( Mouse, intravenous injection), propylene glycol is 21-33.7 g / kg (rat, oral), propylene carbonate 29 g / kg (rat, oral). It is a substance that should seriously consider the problem of various side effects.
The origin of curcumin, its derivatives, and curcuma extract used in the present invention is Curcuma xanthorrhiza, which is traditionally used in Indonesia's folklore for gastric and liver disease, anticancer activity, dysentery, fever, It is known to be excellent in hemorrhoids and constipation. The main ingredients are sesquiterpenoides such as alpha-curcumene, beta-curcumene, beta-curcumene, artumenone, xanthorrhizol, germacrone, beta- Sesquihellandrene (β-sesquiphellandrene), Curzerenone (Curzerenone), alpha / beta-termerone (α- / β-turmerone) and the like.

   Conventional microemulsions require larger amounts of surfactants and cosurfactants than conventional emulsions. Therefore, the formulation of the microemulsion preparation has a basic problem of minimizing the amount of surfactant while maintaining the highest solubility and dissolution rate of the amount of the surfactant, co-surfactant and oil.

   In particular, since the soy medicine containing the main ingredient of silymarin is a component that requires a relatively large amount of the main ingredient, it is easy to be designed to be very inconvenient to take because the size of the formulation is too large when the formulation is designed as a microemulsion. Therefore, in order to design a dosage form in an easy-to-take size, it is a preparation having a problem of minimizing the size of the preparation by minimizing the type and amount of ingredients.

   In addition, microemulsion generally forms a size of about 10-200 nanometers in an aqueous solution, but micelles have a very advantageous advantage in terms of solubility and bioabsorption rate because they exist in an aqueous solution in a size of 2-10 nanometers in a micelle system.

Therefore, the present invention is designed to be easy to take by using a minimum amount of surfactants by completely removing the oil component of the microemulsion, and also to optimize the HLB value to automatically form micelles when exposed to aqueous solutions and biological fluids Automated drug delivery system (Auto Micellization DDS) maximizes the solubility and dissolution rate of drugs, overcomes the formulation instability of microemulsions in which oil can be dissipated over time, and secures oral bioavailability while securing physical and chemical stability. Maximized oral pharmaceutical composition.

   Polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene Block copolymers, macrogol glycerol hydroxystearate, sodium lauryl sulfonate, and the like, and these may be used alone or in combination of two or more thereof.

   Co-solvents alone or in combination, such as propylene carbonate, propylene glycol, ethanol, transcutol (diethylene glycol monoethyl ether), glycofurol (Glycofurol, tetrahydrofurfuryl alcohol polyethylene glycol ether) and polyethylene glycols You can use Of these, propylene carbonate, propylene glycol and polyethylene glycols may be used alone or in combination of two or more thereof.

   The composition of the present invention preferably comprises the above components in a weight ratio of 1: 0.1 to 20: 0.1 to 20: cardus marianus extract and curcuma x: surfactant: cosolvent.

   Pharmaceutically acceptable flavors, preservatives, antioxidants, fragrances, sweeteners, colorants, pH adjusters, viscosity adjusters, and the like can be added to the compositions of the present invention.

   In the method for preparing a composition of the present invention, the hard capsules and soft capsules of which both Cardus Marianus X, a surfactant and a cosolvent are mixed, heated and dissolved at about 80 degrees, and then suspended or dissolved in curcuma extract and gelatin banded in oral formulation. It can be formulated simply by filling into a back, oral solution containing caramel or jelly type chewable tablets and aqueous solution.

   Hereinafter, the present invention will be described in more detail with reference to the following examples. However, this embodiment is for illustrating the present invention and the scope of the present invention is not limited to this embodiment.

   For a thorough understanding of the features and objects of the present invention, reference should be made to the following detailed description of the drawings.

   Figure 1 is a graph showing the rate and amount of drug eluted from the formulation under acidic conditions in the gastrointestinal tract.

   FIG. 2 is a graph showing the rate and amount of drug eluted from the agent under alkaline conditions, particularly in the small intestine and large intestine.

Figure 3 is a graph showing the concentration of the drug in plasma over time showing the comparative oral bioavailability of the reference drug and the soft capsule of Example 1.

Example 1

   Cardus marius extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed and propylene carbonate, polyethylene glycol and propylene glycol are added thereto. After heating to .C and dissolving transparently, curcuma X is mixed after mixing and filling into soft capsule.

<Table 1>

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Curcuma X 50 Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Propylene carbonate 200 Polyethylene Glycol 400 380 Propylene glycol 20

Example 2

    Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed, propylene carbonate is added thereto, and then warmed to 80 ° C. After dissolving, it is filled into soft capsule and formulated.

<Table 2>

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Propylene carbonate 300

Example 3

   Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed and propylene carbonate and polyethylene glycol are added to 80 ° C. After warming and dissolving transparently, it is filled into a soft capsule and formulated.

<Table 3>

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 200 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Propylene carbonate 200 Polyethylene Glycol 400 400

Example 4

   Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) were mixed and propylene carbonate, polyethylene glycol and propylene glycol were added thereto. It is prepared by heating it at ° C and dissolving it transparently and filling it with a soft capsule.

<Table 4>

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Propylene carbonate 200 Polyethylene Glycol 400 380 Propylene glycol 20

Example 5

   Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed, and polyethylene glycol and propylene glycol are added thereto and then warmed to 80 ° C. After dissolving transparently, Curcuma X is mixed after mixing and filling into soft capsule.

<Table 5>

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Curcuma X 50 Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Polyethylene Glycol 400 150 Propylene glycol 300

Example 6

   Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed, and polyethylene glycol and propylene glycol are added thereto and then warmed to 80 ° C. After dissolving transparently, Curcuma X is mixed after mixing and filling into soft capsule.

<Table 6>

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Curcuma X 50 Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Polyethylene Glycol 400 150 Propylene glycol 600

Example 7

   Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed, and polyethylene glycol and propylene glycol are added thereto and then warmed to 80 ° C. After dissolving transparently, curcuma X is mixed after mixing, dissolving by adding white sugar and citric acid flavor, dissolving it with purified water, sterilizing it, and filling it into a 30ml bottle and formulating it in a liquid state.

<Table 7>

ingredient Content (mg) Cardus marianus extract 200-300 (60mg as silybin) Curcuma X 50 Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 200 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Polyethylene Glycol 400 150 Propylene glycol 600 White sugar 10000 Citric acid 30 Spices 5 Purified water Quantity Total amount 30 ml

Example 8

   Cardusmarinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80), and macrogol glycerol hydroxystearate (cremopoa RH 40) were mixed and polyethylene glycol and propylene glycol were added to 80 ° C. After warming and dissolving transparently, Curcuma X is mixed after mixing and filling into soft capsule.

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Curcuma X 50 Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Cremopoa RH 40 200 Polyethylene Glycol 300 150 Propylene glycol 600

Example 9

   Cardus marinus extract, polyoxyethylene sorbitan fatty acid ester (Tween 80) and polyoxyethylene polyoxypropylene block copolymer (poloxamer) are mixed, and polyethylene glycol and propylene glycol are added thereto and then warmed to 80 ° C. After dissolving transparently, Curcuma X is mixed after mixing into a caramel chewable tablet.

ingredient Content (mg) Cardus marianus extract 200 to 300 (60 mg in silbin) Polyoxyethylene Sorbitan Fatty Acid Ester (Twin 80) 350 Polyoxyethylene Polyoxypropylene Block Copolymer (Poloxamer) 200 Polyethylene Glycol 400 380 Propylene glycol 20 McAyon 1000 White sugar 1000 gelatin 100 Sugar 500 corn syrup 100 Spices 5 Citric acid 5

Experimental Example 1                     

Comparative Solubility Experiment

Legacon 140 capsules (Korean Patent Publication No. 1996-0028916) and Legaron 140 capsules, which are provided by Madus, Germany, and marketed in Buwang Pharmaceuticals, as a formulation that has more than doubled the bioavailability of sillibin. Solubility of Silliman 140 soft capsule of Hanmi Pharm (Korea Patent Publication No. 2001-0008804), which is known to have increased bioavailability by more than 2 times, and the soft capsule of Example 1 prepared by an automatic micellization system Comparative tests were performed.

Test Method: 60 mg of silicide was added to each 50ml solution of pH 1.2 and 7.4 buffer under 37 ° C, and the mixture was stirred for a certain time, and then the solubility was measured and compared.

<Table 7> Test Results (Unit: g / ml)

Test formulation pH 1.2 pH 7.4 Legaron 140 11 69 Silliman 140 630 660 Example 1 907 950 Example 1 / Legaron 140 X 100 (%) 8,245% 1,377% Example 1 / Silliman 140 X 100 (%) 145% 145%

The results indicate that the solubility is excellent at both pH 1.2 and pH 7.4 compared to the conventional commercial formulations, it was expected that the formulation of the present invention will be very good bioavailability.

Experimental Example 2

Comparative dissolution test

A dissolution rate comparison test was performed with two control drugs used in Experimental Example 1 and the composition of Example 1.

Test method: 60 mg of silicin was added to each of 750 ml of pH 1.2 and 7.4 buffer solution at 37 ° C, and the mixture was stirred at 100 rpm and paddle method for a certain time.

Test Results: See FIG. 1 (elution pattern at pH 1.2) and FIG. 2 (elution pattern at pH 7.4).

In the dissolution test results, the soft capsule of the present invention prepared using an automatic micelle-forming system showed a rapid and excellent dissolution rate compared to the control drugs as in the solubility test.

Experimental Example 3

Bioavailability Comparison Test

Two control drugs used in Experimental Example 1 and the composition of Example 1 prepared by an automated micelle system were subjected to a comparison of bioavailability using a rat.

Test Methods

   After fasting for 24 hours or more before the start of the test, the drug was dosed at a dose of 60 mg / kg as silicide, and blood samples were analyzed before and after 0.5, 1,1.5, 2, 3, 4, 6, and 8 hours after administration.

The analysis was carried out using the internal standard naringenin and quantified by the free and bound total silybin of the silybin, and compared the bioavailability (see test results Figure 3).

According to the test results, the soft capsule of the present invention prepared using an automatic micellization system has the highest blood concentration and blood concentration even compared to the Silliman 140 soft capsule, which is known to have enhanced absorption rate by about 2 times or more than the Legaron 140 capsule and Legaron 140 capsule. The area under the curve (AUC) is increased. Therefore, it can be seen that the formulation of the present invention shows very good bioavailability.

The composition of the present invention has a very good bioavailability at pH 1.2 and pH 7.4 as compared to the existing formulations, and has a rapid and excellent dissolution rate, as confirmed in Experimental Examples 1 to 3.

Claims (6)

   Cardus marianus extract, or a mixture of Cardus marianus extract and Curcuma extract as an active ingredient; At least one surfactant selected from polyoxyethylene sorbitan self-protecting acid ester, polyoxyethylene polyoxypropylene block copolymer and macrogol glycerol hydroxystearate; An oral composition comprising at least one co-solvent selected from propylene carbonate, propylene glycol and polyethylene glycol 400 in a weight ratio of 1: 1 to 6: 1 to 6. delete delete delete    The composition of claim 1, which contains at least one pharmaceutically acceptable additive selected from the group consisting of flavoring agents, sweetening agents, pH adjusting agents, antioxidants, preservatives and stabilizers.    The composition of claim 1 is formulated as a soft capsule, hard capsule, caramel, and jelly type chewable or liquid formulation as an oral dosage form.

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