KR20080105632A - Liposome preparation containing germanium and manufacturing method thereof - Google Patents

Abstract

An organic germanium composition, and a method for preparing an organic germanium preparation are provided to improve the absorption to the skin and to enhance stability. An organic germanium composition comprises the liposome containing an organic germanium as an active ingredient. Preferably the organic germanium is represented by the formula 1. Preferably the liposome is prepared from a mixture comprising a phospholipid, an oily component, a polyol, a surfactant and water. Preferably the liposome comprises further ceramide.

Description

Germanium-containing liposome preparation and method for preparing same

The present invention relates to germanium-containing preparations and methods for their preparation.

Germanium is an off-white, shiny, semi-metallic element composed of 32 electrons, a hard and brittle crystal with specific gravity of 5.3, atomic weight of 72.59, and melting point of 958.5 degrees Celsius. As a semiconductor, germanium has made a significant contribution to the development of electronics, and it also shows the mysterious efficacy of treating cancer and other diseases by strengthening natural healing power by acting on the human body, which is an aggregate of ultrafine particles of electricity. Germanium can be divided into inorganic germanium and organic germanium. Inorganic germanium is known to show strong toxicity to the human body when ingested. However, there are no reports of harmful effects on organic germanium, and it has been reported to have various beneficial effects on the human body.

Organic Germanium was first synthesized in 1968 by Japanese scientist Dr. Asai, and is present in small amounts in ginseng, garlic, ganoderma lucidum, wolfberry, and yulmu. Organo germanium has shown some recognized medical effects in Japan, and 2g daily oral administration has been reported to partially cure or cure viral infections, circulatory diseases, and malignant tumors (K. Asai Miracle cure : Organic Germanium, Japan Publications Inc ISBN 0-87040-1, 1980).

As a result of the recent scientific investigation of the efficacy, very effective interferon induction function, immunomodulatory activity, and antitumor effect have been reported (M. Tsutui. Et al., J. Am Chem. Soc. 98, 8278-). 8289 (1976), H Aso, et al., Microbiol. Immunol. 29, 65-74 (1985), and F. Suzuki RR Brutkiewicz aud RB Pollard, Anticancer Res. 6, 177-183 (1986). As such, many studies on organic germanium have been conducted to date, and there are many patents and reports on the effects thereof, and representative examples include anti-wrinkle effect, acne relieving and healing effect by promoting collagen synthesis, antioxidant effect showing radical scavenging ability, It has been reported to protect against UV damage, soften skin, improve abnormal pigmentation, and treat atopic dermatitis (Korean Patent Nos. 10-2001-0075747, Japanese Patent No. 63183570, Japanese Patent No. 6211908, US Pat. No. 4,229,468, US Pat. No. 4,895,715, US Pat. No. 4,637,67, K. Asai Miracle cure: Organic Germanium, Japan Publications Inc ISBN 0-87040-1, 1980).

Such organogermanium is known as a single form, which is not easy to be absorbed in vivo when directly ingested or used externally, and the inclusion stability of an agent containing organogernium is poor.

Therefore, the technical problem to be achieved by the present invention is to provide an organic germanium formulation and its preparation method which have improved stability and improved in vivo absorption at the time of ingestion or external use.

In order to achieve the above technical problem, the present invention provides an organic germanium composition with improved stability and bioabsorption, characterized in that it comprises a liposome containing an organic germanium as an active ingredient.

More preferably, the present invention provides a composition, wherein the liposomes described above are prepared by a mixture comprising a phospholipid, an oily component, a polyol, a surfactant, and water.

Preferably, the present invention provides a composition, wherein the liposomes described above are stabilized with oligosaccharides, and more preferably, the oligosaccharides are fucoidans.

The present invention also includes the step of passing a mixture containing phospholipids, oil phase components, polyols, surfactants, water and organo germanium through a High Pressure Homogenizer to produce liposomes containing organo germanium. To provide a method for preparing an organo germanium-containing preparation having improved stability and bioabsorption, and more preferably, the preparation method further comprises the step of mixing the prepared liposomes and oligosaccharides. .

Hereinafter, an organic germanium preparation having improved stability and bioabsorption, and a method for preparing the same, comprising the organic germanium-containing liposome according to the present invention as an active ingredient will be described in more detail.

The present invention is based on the surprising finding that the formulation of organogermanium by liposome techniques improves stability and in vivo absorption. Therefore, the present invention provides an organic germanium composition having improved stability and bioabsorption, comprising an organic germanium-containing liposome as an active ingredient.

The organic germanium added to the present invention is biscarboxyethyl germanium sesquioxide, whose structural formula is (GeCH ₂ CH ₂ C00H) ₂ O ₃ , and the structure thereof is represented by the following Chemical Formula 1. For example, such organic germanium may be commercially available from the UK under the trade name Arlamol GEO from ICI, Inc., but the present invention is not limited thereto.

The mixed amount of the organic germanium used for preparing the organic germanium-containing liposome of the present invention is preferably used in an amount of 5 to 20% by weight based on the total weight of the water-containing mixture for preparing the liposome, and more preferably in an amount of 15 to 18% by weight. Do.

The organic germanium-containing liposomes, which are the active ingredients of the organic germanium composition of the present invention, may be prepared by a mixture containing phospholipids, oily components, polyols, surfactants, and water.

As the phospholipid used in the preparation of the liposome of the present invention, various phospholipids known in the art may be used. Toil phosphatidylcholine and the like can be used one or more. Such phospholipid is preferably 2 to 20% by weight relative to the total weight of the water-containing mixture for preparing liposomes.

As the oil component used to prepare the liposome of the present invention, various oils known in the art may be used, for example, hydrocarbon-based oils such as hexadecane and paraffin oil; Synthetic synthetic oils such as isopropyl myristate; Silicone oils such as dimethicone and cyclomethicone series; Animal and vegetable oils such as sunflower oil, corn oil, soybean oil, avocado oil, sesame oil, jojoba oil, nut oil, squalane and fish oil; Ethoxylated alkyl ether oils; Propoxylated alkyl ether oils; Sphingoidoid lipids such as phytosphingosine, sphingosine and sphinginine; Cerebroside; cholesterol; Cytosterol; Cholesteryl sulfate; Cytosteryl sulfate; One or more C _10-40 fatty alcohols may be used, and preferably, macadamia nut oil, meadowfoam seed oil, sunflower oil, phytosqualane, or the like may be used. This oil phase component is preferably used in 5 to 20% by weight, more preferably 10 to 15% by weight relative to the total weight of the water-containing mixture for preparing liposomes.

The present invention also uses a polyol as an emulsion stability aid in the preparation of liposomes, such polyols are propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, methyl propanediol, isoprene glycol, pentylene glycol, Erythritol, xylitol, sorbitol and the like can be used, and such polyols are more preferably glycerin, butylene glycol, propylene glycol, and the like. Such polyols are preferably used in an amount of 2 to 15% by weight, more preferably 5 to 10% by weight, based on the total weight of the water-containing mixture for preparing liposomes.

The present invention also uses surfactants for the preparation of liposomes. As the surfactant, any known in the art may be used. For example, anionic surfactants, cationic surfactants, amphoteric surfactants or nonionic surfactants may be used, and preferably anionic surfactants. Or nonionic surfactants are used. Specific examples of anionic surfactants include alkylacylglutamate, alkylphosphates, alkyllactylates, dialkylphosphates, alkyllactates and trialkylphosphates. Specific examples of nonionic surfactants include alkoxylated alkyl ethers, alkoxylated alkyl esters, alkylpolyglycosides, polyglyceryl esters and sugar esters. More preferably, the surfactant is diecetyl phosphate. The content of the surfactant is preferably used in an amount of 0.5 to 1.5% by weight, more preferably 0.8 to 1.0% by weight, based on the total weight of the water-containing mixture for preparing liposomes.

More preferably, the present invention further utilizes ceramides for the preparation of liposomes, wherein the ceramides are preferably from 0.01 to 0.5% by weight relative to the total weight of the water-containing mixture for preparing the liposomes. These ceramides can promote more percutaneous absorption due to their superior skin affinity as lipid components between cells.

The present invention is also based on the surprising finding that mixing with oligosaccharides after the preparation of liposomes improves the stability of the organogerium-containing liposomes according to the present invention and the bioabsorption of organogerium.

Fucoidan, glucosamine, pectin, heparin and the like may be used as such oligosaccharides, and fucoidan is most preferred. The content of such oligosaccharides is preferably used 5 to 15% by weight, more preferably 10 to 12% by weight relative to the total weight of the water-containing mixture for preparing liposomes.

The liposome of the present invention can be extruded through a filter having a straight passage or a curved passage, or homogenized using a homogenizer to have a reduced uniform size distribution, and the prepared solution is dried by dehydration or lyophilization. You can.

The liposomes of the present invention are multi lamella vesicle liposomes with a preferred diameter of 50 to 100 nm and most preferably about 70 to 90 nm, because the biological cell gap has an average of 80 nm and organo germanium incorporation capacity at these sizes. And because it can maximize bioabsorption.

As a result, the present invention includes the step of passing a mixture containing phospholipids, ceramides, oil components, polyols, surfactants, water, and organic germanium through a High Pressure Homogenizer or the like to prepare liposomes containing organic germanium. It provides a method for producing an organo germanium-containing preparation having improved stability and bioabsorption, characterized in that the method further comprises the step of mixing with the prepared liposomes and oligosaccharides.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Production of Organic Germanium-containing Liposomes>

To prepare a liposome preparation containing an organo germanium according to the composition and content of Table 1. Measure the raw materials 1 and 2 of Table 1 in a separate beaker, heat and dissolve at 90-105 ° C., cool to 80 ° C., heat dissolve raw materials 3 to 5 at 80 ° C., and mix with raw materials 1 and 2. It is then sealed and moistened for 30 minutes. After cooling to 40 ° C. and stirring and dispersing with a homomixer while adding 6 raw materials, 7-8 raw materials were added and dispersed for 3 minutes with a homomixer, and then passed through a microfluidizer to pass MLV liposomes (1 Tea capsules). The pressure of 800 bar to 1000 bar was optimal for preparing liposomes using a high pressure homogenizer. As a result, the number of passage of the high pressure homogenizer used in the present invention was one to three times.

Raw material (unit: weight%) Formulation Example 1 Formulation Example 2 Formulation Example 3 Formulation Example 4 Formulation Example 5 1. Soy Lecithin 2.0 8.0 10.0 15.0 20.0 2. Ceramide 0.01 0.1 0.3 0.4 0.5 3. Purified water 40 40 40 40 40 4. Glycerin 5.0 7.0 10.0 10.0 10.0 5. D. Acetylphosphate 0.5 0.8 1.0 1.0 1.0 6. Macadamia Nut Oil 5.0 10.0 10.0 10.0 15.0 7. Purified water to 100 to 100 to 100 to 100 to 100 8. Organic Germanium 5 10 15 18 20

Liposomes were rarely produced when the content of phospholipid base was 2% by weight (Formulation Example 1), and liposomes were made excellent at 20% by weight (Formulation Example 5). In the ceramide, stable liposomes were formed at the content of 0.01-0.5% by weight, and the multilamellar form was excellent as the content increased. The amount of ceramide used in general cosmetics is known to be 0.05-0.1% by weight.

Preparation of Oligosaccharide Matrix Double Capsule

As shown in Table 2 below, the primary MLV liposome (raw material 1) was accurately weighed in a 1 liter beaker, and then mixed with an oligosaccharide fucoidan, followed by a homomixer in a range of 1 to 10 minutes to allow sufficient dispersion. Stirred. At this time, the stirring speed varies depending on the amount of contents, but generally, stirring at 1,000 to 2,000 rpm was appropriate.

Raw material name Example 1 Example 2 Example 3 Example 4 Example 5 1. Liposomes (Formulation Example 4) 97.0 95.0 93.0 90.0 85.0 2. Oligosaccharide (50% aqueous solution) 3.0 5.0 7.0 10.0 15.0

<Elution Evaluation of Organic Germanium from Liposomes>

Preparations containing organic germanium were prepared and quantitatively analyzed by atomic absorption spectrometer after 6 months at 35 ° C. The results are shown in Table 3 below.

The liposome method shown in Table 3 below is an evaluation result using the organic germanium liposome preparation prepared in Formulation Example 4, and the oligosaccharide mixing method is the result of using the liposome preparation to which the oligosaccharides prepared in Example 5 are added, and the general emulsification method. Was prepared according to a conventional emulsification method using glyceryl stearate / pG-100 stearate, glyceryl stearate SE, sorbitan stearate / sucrosecoate, cetyl alcohol and macadamia nut oil as raw materials. .

Raw material name (unit: weight%) Initial content (% by weight)  General emulsification method (% remaining)  Liposome method (% remaining) Oligosaccharide mixing method (% remaining) germanium 15 2 12.5 14.5 (Example 5)

As shown in Table 3, the residual amount of the organic germanium preparation using the general emulsification method was only 2% after 6 months, but the residual amount of the liposome preparation containing the organic germanium was much higher than that of the general emulsification method. In addition, formulations with additional fucoidans formed very stable formulations with little loss of organogermanium.

<Organic Germanium's Skin Acupuncture Effect>

Insert fresh pig skin (similar to human skin) between the upper and lower cylindrical tubes, place a certain amount of sample on the upper layer of the pig skin, and put the saline (corresponding to the blood of the living body) on the lower layer of the pig skin with a magnetic stirrer. The amount of germanium permeated from the upper part to the lower part through the pig skin at regular intervals while rotating (similar to blood flow) was analyzed by atomic absorption spectrometer to observe the level of transdermal absorption. The results after 48 hours after the start of the experiment are shown in Table 4 below.

 General oil painting  Liposome method When mixing liposomes and oligosaccharides Germanium level before starting experiment on upper layer 15% 15% 15% Germanium amount transmitted through lower layer 2% 9% 11%

As shown in Table 4, when the liposome method and the oligosaccharide mixture are superior to the absorption rate by the general emulsification method, the transdermal absorption degree is excellent, and thus the absorption effect in the living body can be expected.

As described above, the present invention improved the skin absorption rate by formulating germanium liposomes, this improvement can be applied to a variety of skin external preparations, food, medicine, cosmetics and the like. In addition, when the oligosaccharides are mixed with the organo germanium liposome preparation, the stabilization and bioabsorption rate of the liposomes are greatly improved.

Claims (14)

An organic germanium composition having improved stability and bioabsorption, comprising a liposome containing an organic germanium as an active ingredient. According to claim 1, wherein the organic germanium is a composition characterized in that represented by the formula (1). <Formula 1>

The composition of claim 1, wherein the liposome is prepared by a mixture comprising a phospholipid, an oily component, a polyol, a surfactant, and water. The composition of claim 3, wherein the phospholipid is at least one selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and dipalmitoylphosphatidylcholine. The composition of claim 3, wherein the liposome is prepared by a mixture further comprising ceramide. According to claim 3, The oil phase component is a hydrocarbon-based oil; Synthetic synthetic oils; Silicone oils; Animal and vegetable oils; Ethoxylated alkyl ether oils; Propoxylated alkyl ether oils; Sphingoidoid lipids; Cerebroside; cholesterol; Cytosterol; Cholesteryl sulfate; Cytosteryl sulfate; And C _10-40 fatty alcohol, characterized in that any one or more selected from the group consisting of. The method of claim 3, wherein the polyol is at least one selected from the group consisting of propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, methyl propanediol, isoprene glycol, pentylene glycol, erythritol, ziitol and sorbitol A composition, characterized in that. The method of claim 3, wherein the surfactant is an anionic surfactant group consisting of alkylacyl glutamate, alkyl phosphate, alkyl lactylate, dialkyl phosphate and trialkyl phosphate; And a nonionic surfactant group consisting of alkoxylated alkyl ethers, alkoxylated alkyl esters, alkylpolyglycosides, polyglyceryl esters, and sugar esters. The composition of claim 1 or 3, wherein the liposomes are stabilized with oligosaccharides. 10. The composition of claim 9, wherein the oligosaccharide is fucoidan. A mixture containing phospholipids, oily ingredients, polyols, surfactants, water, and organic germanium is passed through a High Pressure Homogenizer to prepare liposomes containing organic germanium. A method for preparing an organo germanium-containing formulation having improved water absorption. The method of claim 11, wherein the method further comprises mixing the prepared liposomes with oligosaccharides. The method of claim 12, wherein the oligosaccharide is fucoidan. The method of claim 11, wherein the mixture further comprises ceramide.