KR20160149400A - Liquid composition for oral administration having liposomes that encapsulate EDTA and Vitamine C - Google Patents
Liquid composition for oral administration having liposomes that encapsulate EDTA and Vitamine C Download PDFInfo
- Publication number
- KR20160149400A KR20160149400A KR1020150086293A KR20150086293A KR20160149400A KR 20160149400 A KR20160149400 A KR 20160149400A KR 1020150086293 A KR1020150086293 A KR 1020150086293A KR 20150086293 A KR20150086293 A KR 20150086293A KR 20160149400 A KR20160149400 A KR 20160149400A
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- KR
- South Korea
- Prior art keywords
- edta
- liquid composition
- aqueous solution
- vitamin
- oral administration
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/02—Acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/70—Vitamins
- A23V2250/708—Vitamin C
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Abstract
The present invention relates to a liquid composition for oral administration containing a liposome encapsulated with EDTA and vitamin C, which can be easily taken orally to remove vascular waste and can be easily taken by patients who are unable to take a solid preparation.
Description
The present invention relates to a liquid composition for oral administration containing a liposome encapsulated with EDTA and vitamin C, and more particularly, to a liquid composition for oral administration containing EDTA and vitamin C encapsulated therein, which can improve the ease of taking the solid preparations, ≪ RTI ID = 0.0 > EDTA < / RTI >
EDTA (ethylenediaminetetraacetic acid) is a compound that has strong affinity with metal ions. Due to the characteristics of EDTA, EDTA is used in various industrial fields for metal ion removal.
Vitamin C (Viramin C, ascorbic acid) increases the immunity of the body and promotes the collagen fish to prevent skin damage caused by ultraviolet rays. It acts as a strong antioxidant to remove active oxygen harmful to the human body and prevent aging. And it has the effect of detoxifying the poison accumulated in the human body. However, vitamin C is a nutrient that should be ingested regularly because it can not synthesize itself in our body.
Recently, exposure to harmful heavy metals due to environmental pollution and toxic substances in the blood vessels caused by high-diet eating habits, and toxins in the body caused by them have been harmful to modern people's health, so that contaminated heavy metals, fats and arteriosclerosis substances in the blood can be removed EDTA, a chelating agent, and vitamin C, a potent detoxifying agent, are attracting attention in the medical field.
EDTA chelation therapy is a method of administering EDTA, vitamins, and trace element combinations via intravenous injection and expelling EDTA and adsorbed body waste to the urine. This treatment was initially used for the treatment of diseases such as lead and heavy metal poisoning (Ernst E., Chelation therapy for peripheral arterial occlusive disease: A systemic review, Circulation: 96: 1031-3, 1997) (EDTA chelation therapy in cardiovascular disease, Master's Thesis, Department of Alternative Medicine, College of Medicine, 2008). The EDTA chelation treatment method can be safely used according to a treatment program made by clinical experience (Cranton EM., A textbook on EDTA chelation therapy., Hampton Road Publishing Company; 2nd edition., 2001.04) And vitamins, etc. Slowly administer the solution for 3 to 4 hours to the vein for 3 to 4 hours, with 3 g of EDTA in 500 cc of the solution. It is known that intravenous administration can be achieved by intravenous administration 30-40 times a week for 1-2 weeks (Green S, Sampson W, et al., J Hepatol. Winter 2002 issue). However, the administration of EDTA is important for safe treatment because EDTA can cause side effects such as hypotension, headache, arrhythmia, and kidney damage if administered too rapidly into the vein (Guldager B et al., EDTA treatment of intermittent claudication a double-blind, placebo-controlled., J Int Med; 231 (3): 261-267, 1992).
Typical methods of administration of the drug include intravenous administration using an injection and oral administration using a solid preparation. Intravenous administration is the best method in case of emergency because the drug is distributed at a high concentration and the action is the fastest. However, once the drug is administered, it can not be reversed, and repeated injections are more likely to become infected with phlebitis. On the other hand, the oral administration method is advantageous in that it is easy to administer, has few side effects, and does not need professional manpower. However, drugs that are destroyed by gastric and digestive enzymes or drugs with low water absorption in the small intestine are not appropriate for oral administration. In addition, oral solid preparations are difficult to take by people who are hard to swallow solid preparations such as children and the elderly, and the amount of the composition can not be subdivided into appropriate doses depending on the weight of liquid preparations. The EDTA chelation treatment method shows a good oral administration method in terms of repeated administration of about 30-40 times and a great risk due to the administration rate, but there is a problem in efficiency because the small intestine absorption rate of EDTA is poor when administered orally.
Liposomes are artificially produced vesicles composed of one or more phospholipid bilayers. The liposome has a hydrophilic space in the inside and a double lipid membrane closed to the outside, so that water-soluble molecules or drugs can be contained in the hydrophilic space, lipophilic drugs can be attached to the external lipid bilayer, and positive and negative substances can be bonded have. The reason that liposomes of this nature are useful for drug delivery is that the drug is protected in the double membrane to prevent the destruction by enzymes in the blood and the liposome can play a role in delaying drug release. In addition, liposomes can be easily modified to direct therapeutic substances to target cells or to prevent them from going to specific sites (Kosaraju SL, Tran C, Lawrence A. Liposomal delivery systems for encapsulation of ferrous sulfate: preparation and characterization. J Liposome Res., 16 (4): 347-58., 2006.).
The kidneys remove water and minerals from the body, secrete toxic metabolites, maintain acid-base balance, and control the electrolyte and mineral levels within the physiological range. However, if kidney disease is caused by kidney disease, urine toxic metabolites including urine, urea, creatinine and uric acid accumulate in the blood as urine to be discharged to the outside of the body, thereby reducing the overall function and recovery ability of the organism. In severe cases, . Therefore, it is necessary to lower the level of high blood waste in the treatment and prevention of kidney disease. Currently, hemodialysis and peritoneal dialysis are performed, but it is troublesome to visit the hospital or use the machine every time.
The present invention relates to a vitamin C delivery system and a liposome composition for enhancing the bioavailability of vitamin C when the composition is orally administered by enclosing vitamin C in a liposome. The present invention also relates to a method for preparing an EDTA liposome composition for oral administration, wherein the EDTA liposome composition for oral administration is encapsulated in a liposome and is stable upon oral administration and effectively chelates waste materials in the body. The formulation of the composition is an oral solid preparation such as tablets, capsules and powders, and does not contain vitamin C.
Therefore, a liquid preparation that can be orally administered with EDTA and vitamin C is required, and it is not known.
Accordingly, an object of the present invention is to provide a liquid composition for oral administration containing EDTA and vitamin C-encapsulated liposomes that are stable at oral administration and can effectively chelate vascular waste and can be easily taken by patients who are unable to take a solid preparation Method.
It is another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of renal diseases containing the composition prepared by the above-mentioned method as an active ingredient.
It is still another object of the present invention to provide a functional food composition for preventing and improving renal diseases, which comprises the composition prepared by the above-described method as an active ingredient.
The object of the present invention is to provide a liquid preparation for oral administration containing 94.6 mL of purified water and containing 30 g of calcium disodium EDTA, 5 g of magnesium, 30 g of ascorbic acid, 7 g of potassium sorbate and 30 g of sunflower lecithin and EDTA and vitamin C encapsulated liposomes (A) dissolving 30 g of Calcium Disodium EDTA in 237 mL of purified water and stirring for 20 minutes to prepare an aqueous solution of calcium disodium EDTA (1); (b) dissolving 5 g of Magnesium in purified water (133 mL) and stirring for 20 minutes to prepare a magnesium chloride aqueous solution (2); (c) dissolving 30 g of ascorbic acid in 237 mL of purified water and stirring for 20 minutes to prepare an aqueous solution of vitamin C (3); (d) dissolving 30 g of Sunflower lecithin and 7 g of potassium sorbate in 339 mL of purified water and stirring for 25 minutes to prepare an aqueous solution of lecithin (4); (e) The aqueous solution of calcium disodium EDTA (1), the aqueous solution of magnesium chloride (2), the aqueous solution of vitamin (3) and the aqueous solution of lecithin (4) obtained in the above steps were stirred for 30 minutes, mixed again with an ultrasonic cleaner A liquid composition for oral administration is prepared containing liposomes containing EDTA and vitamin C, and the ability of the liquid composition obtained in the above step to chelate the waste matter in blood vessels as a test substance is evaluated.
INDUSTRIAL APPLICABILITY According to the present invention, there is an effect that a liquid composition containing liposome encapsulated with EDTA and vitamin C is orally administered to provide a convenient patient to take a solid preparation while effectively chelating vascular waste, There is an effect of providing a pharmaceutical composition for the prevention and treatment of kidney disease or a functional food composition for the prevention and improvement of kidney disease.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing BNU levels in blood after oral administration of a liquid composition for oral administration containing EDTA and vitamin C encapsulated liposomes according to the present invention to a mouse model of glomerular nephropathy. FIG.
FIG. 2 is a graph showing blood creatinine levels after oral administration of a liquid composition for oral administration containing EDTA and vitamin C encapsulated lipase of the present invention to a mouse model of glomerulopathies.
Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples, but it goes without saying that the scope of the present invention is not limited thereto.
(A) dissolving 30 g of Calcium Disodium EDTA in 237 ml of purified water and stirring for 20 minutes to prepare an aqueous solution of calcium disodium EDTA (1); (b) dissolving 5 g of Magnesium in purified water (133 mL) and stirring for 20 minutes to prepare a magnesium chloride aqueous solution (2); (c) dissolving 30 g of ascorbic acid in 237 mL of purified water and stirring for 20 minutes to prepare an aqueous solution of vitamin C (3); (d) dissolving 30 g of Sunflower lecithin and 7 g of potassium sorbate in 339 mL of purified water and stirring for 25 minutes to prepare an aqueous solution of lecithin (4); (e) The aqueous solution of calcium disodium EDTA (1), the aqueous solution of magnesium chloride (2), the aqueous solution of vitamin (3) and the aqueous solution of lecithin (4) obtained in the above steps were stirred for 30 minutes, mixed again with an ultrasonic cleaner .
A feature of the present invention is to prepare a liquid composition having EDTA and vitamin C encapsulated in liposome, which has a stable effect and an excellent killing effect in a blood vessel, and orally administers it. Liposomes and methods for preparing liquid compositions are well known in the art, but generally there is a great difference in the stability and biological properties depending on the materials, solvent, addition amount, and order of addition, mixing and stirring conditions of the liposome and the liquid composition, have.
INDUSTRIAL APPLICABILITY The liquid composition for oral administration containing a liposome encapsulated with EDTA and vitamin C is an effective ingredient of a pharmaceutical composition or food composition intended to treat, prevent and improve vascular waste caused by kidney disease It will be apparent to those skilled in the art that the present invention can be used without departing from the scope of the present invention.
The liquid composition for oral administration may be used as a pharmaceutical composition for the prevention and treatment of kidney disease, and may further comprise a pharmaceutically acceptable water-soluble additive. As the water-soluble additive, a buffering agent such as citric acid, sodium citrate hydrate, potassium citrate or acetic acid, or a sweetener such as white sugar, acesulfame potassium, saccharin or dextrose may be added.
In addition, the liquid composition for oral administration may be used as a functional food composition for preventing and improving kidney disease, and may further include a water-soluble additive which is usually added to food. Examples of the water-line additive include vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and heavies (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, Colloid thickening agents, pH adjusting agents, stabilizers, preservatives and the like.
Such renal diseases include renal failure, glomerulonephritis, polycystic kidney disease, nephrotic syndrome, renal vascular disease, nephritis, lupus, neuralgia, porter syndrome, hypoplasia, and hypoplasia.
Such wastes are substances which are left in the body without releasing substances such as creatinine and blood urea nitrogen, which are naturally released after metabolism in the body, and cause physiological imbalance in the human body.
Hereinafter, embodiments will be described in detail. The following examples are for illustrative purposes only and are not intended to limit the invention.
Example 1 Preparation of oral liquid composition containing liposome encapsulating EDTA and vitamin C of the present invention
The oral liquid composition containing the liposome encapsulated with EDTA and vitamin C according to the present invention most preferably has the composition ratio shown in Table 1 below.
EDTA and
Vitamin C
Enclosed
Liposomes
Containing
Liquid formulation
The aqueous solution (2)
The aqueous solution (3)
The aqueous solution (4)
The inventors of the present invention prepared a liquid composition containing the liposome encapsulated with the EDTA of the present invention and vitamin C according to the composition of Table 1 above. First, 30 g of Calcium Disodium EDTA was dissolved in 237 mL of purified water and stirred for 20 minutes to prepare an aqueous solution of calcium disodium EDTA (1). Next, 5 g of Magnesium was dissolved in 133 mL of purified water and stirred for 20 minutes to prepare a magnesium chloride aqueous solution (2). 30 g of ascorbic acid was dissolved in 237 mL of purified water and stirred for 20 minutes to prepare an aqueous solution of vitamin C (3). 30 g of Sunflower lecithin and 7 g of potassium sorbate were dissolved in 339 mL of purified water and stirred for 25 minutes to prepare an aqueous solution of lecithin (4). The aqueous solution of calcium disodium EDTA (1), the aqueous solution of magnesium chloride (2), the aqueous solution of vitamin (3) and the aqueous solution of lecithin (4) obtained in the above steps were stirred for 30 minutes and then mixed with an ultrasonic cleaner for 20 minutes. A liquid composition containing liposomes encapsulating EDTA and vitamin C was prepared.
Comparative Example. 1-3
(Comparative Example 1), phosphatidylcholine (PC) was added instead of sunflower lecithin (Comparative Example 2), sunflower lecithin (Sunflower lecithin) was replaced with soybean lecithin (Comparative Example 3) to which soybean lecithin was added as a control group, and a liquid composition was prepared according to Example 1.
Experimental Example 1. Evaluation of stability of EDTA and vitamin C in the liquid composition of the present invention
The liquid composition prepared according to Example 1 and Comparative Examples 1 to 3 was placed in a high density polyethylene (HDPE) bottle and stored for one month at a body temperature of 36.5 DEG C and a severe condition of 60 DEG C. The analytical method was an HPLC of Waters , The weight of EDTA and vitamin C in the liposome composition was quantified, and the residual amount calculated as a percentage based on the weight of EDTA and vitamin C used in the preparation was quantified in the following Table 2. EDTA in the liposome was measured at a flow rate of 1.58 mL / min using a detector at a wavelength of 258 nm and a Luna C18 column of a phenomenex company using E. The amount of EDTA was relatively determined by plotting the standardized calibration graph using the measured residual amount and the peak at 266 nm of the ultraviolet spectroscope. Vitamin C in the liposome was measured at a flow rate of 0.8 mL / min using a detector wavelength of 254 nm and a Luna C18 column of the phenomenex company. The amount of vitamin C was relatively determined after drawing the standard calibration graph using the measured residual amount and peak at 266 nm of UV spectroscope. The ultraviolet spectrometer was a Helios β model of spectronic unicam.
As can be seen from the above Table 2, it was confirmed that the liquid composition of Example 1 of the present invention had higher stability of EDTA and vitamin C than the liquid compositions of Comparative Examples 1 to 3.
Comparative Example. 4 to 5
A liquid composition was prepared according to the same manner as in Example 1, except that no vitamin C was added (Comparative Example 4) and no calcium disodium EDTA was added (Comparative Example 5) This was used as the disclosure material of Experimental Example 2.
Experimental Example 2. Chelation Effect in Animal Model of Glomerular Nephropathy (FSGS)
In order to examine the chelating effect of oral liquid composition containing EDTA and vitamin C encapsulated liposomes, the liquid composition was orally administered to mouse model of glomerulosclerosis (FSGS) disease, and creatinin (Cr ) And blood urea nitrogen (BUN) levels.
The glomerular nephropathy is also known as glomerulonephritis. It is an abnormality of glomerular defect due to glomerular filtration of blood in the kidney. The diagnosis is made by analyzing the concentration of blood urea nitrogen (BUN) and creatinine (Cr) .
As a test group, 5 mice of FSGS disease BALB / c mice (body weight 19 ~ 21g) were orally administered with 200ul of the liquid composition of Example 1 on the first day and every 3 days for 7 days for 21 days in total. As a disease control group, 200 정 of purified water was orally administered to five FSGS-diseased BALB / c mouse models at the same frequency as the above-mentioned experimental group. As a normal control group, 200 정 of purified water was added to three normal BALB / c mice, Were used. As a control group, 200 μl of the liquid composition of Comparative Example 4 and Comparative Example 5 was orally administered at the same frequency as the above-mentioned experimental group. All animal experiments and animal care were conducted by the NIH Guide. Mice were sacrificed at 7th day, 14th day and 21st day after the first oral administration and blood was collected and centrifuged to obtain serums. Using the serum as a sample, creatinine was measured by picric acid colorimetric kit (Sigma 555-1) and blood urea nitrogen was measured by Urease assay kit (Sigma 640-5).
As shown in FIG. 1, the oral administration of the liquid composition of Example 1 of the present invention showed a decrease in BNU levels compared to the disease control group after 7 days of the first administration and a BNU value similar to that of the normal control group after 21 days. Also, as shown in FIG. 2, the creatinine level of the test group was decreased from 7 days after the first administration to that of the disease control group, and the creatinine level was similar to that of the normal control group after 21 days. In addition, the experimental group to which the liquid composition of the present invention was administered showed a better effect of reducing BUN and creatinine level after 21 days of administration than the control group of the liquid composition of Comparative Example 4 and Comparative Example 5. It has been confirmed through this that the liquid composition for oral administration containing liposomes containing the EDTA and vitamin C of the present invention effectively chelates and excretes BUN and creatinine in the blood during oral administration and that the liquid preparation contains only EDTA The chelating effect was better than the liquid formulation.
<Experimental Example 3> Toxicity test in normal animals
In order to examine the safety of the oral composition for oral administration containing the EDTA and vitamin C encapsulated liposomes, the toxicity test was carried out on six female rats weighing 200 g. The experimental group was injected with 2 mL of the liquid composition of Example 1 through the tail vein. The control group administered an additional three animals with purified water. Toxicity test results As shown in Table 3, SGOT and SGPT and AP values were not significantly different among the blood chemistry values before and after the injection of the control and experimental groups.
SGOT, SGPT and AP are enzymes in hepatocytes. When liver damage occurs, these enzymes are excreted in the blood and the blood level is increased, and it is possible to judge whether or not they are toxic.
EXPERIMENTAL EXAMPLE 4 Clinical Effect of the Liquid Composition for Oral Administration of the Present Invention
The liquid composition prepared according to Example 1 of the present invention was subjected to clinical tests. Clinical trial participants were patients with severe renal disease who were all 50 years old (CASE # 1), 61 year old male (CASE # 2) and 63 year old female (CASE # 3) The subjects took 10 mL of the liquid composition of the present invention having the composition of Example 1 once a day and blood test before and 60 days after taking the test.
Male (CASE # 2)
Female (CASE # 3)
Normal value (unit)
As shown in Table 4, a 50-year-old male (CASE # 1) had a BNU value of 52> 38, a Creatinine value of 8.73> 5.86, and a Uric Acid value was 7.1> 4.6. In a 61-year-old male (CASE # 2), blood tests showed that BNU levels were 83> 62, creatinine levels were 3.40> 2.1, and eGFR levels were 7.1> 4.6. In a 63-year-old woman (CASE # 3), the BNU level was 43.4> 28 and the eGFR level was 21> 25 as a result of hematologic tests. The renal function of the three patients with renal disease was improved after taking the EDTA liposome product. In addition, no abnormal symptoms such as vomiting, fever and dizziness due to the use of the liquid preparation of the present invention were observed at all. Herein, eGFR is an estimated Glomerular Filtration Rate (MDRD) calculated by the Modification of Diet in Renal Disease Is above 90 (mL / min / 1.73) and this value is lowered when the renal function is bad. The results of the above Table 4 demonstrate that the liquid composition of the present invention can be effectively chelated and discharged to the outside of the body during oral administration, such as blood BNU and creatinine.
The present invention has the effect of improving the convenience for taking patients who are hard to take as a solid preparation by oral administration of a liquid composition of EDTA and vitamin C and also has an excellent effect on the removal of waste matter in blood vessels, It is a very useful invention.
Claims (5)
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| KR102565469B1 (en) | 2022-08-31 | 2023-08-16 | 주식회사 한국리포좀 | Vitamin C Encapsulated Liposome and Preparation Thereof |
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| KR102565469B1 (en) | 2022-08-31 | 2023-08-16 | 주식회사 한국리포좀 | Vitamin C Encapsulated Liposome and Preparation Thereof |
| KR20240031041A (en) | 2022-08-31 | 2024-03-07 | 주식회사 한국리포좀 | Vitamin C Encapsulated Liposome and Preparation Thereof |
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