WO2009011520A2 - Nano-particles containing calcium and method for preparing the same - Google Patents

Nano-particles containing calcium and method for preparing the same Download PDF

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Publication number
WO2009011520A2
WO2009011520A2 PCT/KR2008/004080 KR2008004080W WO2009011520A2 WO 2009011520 A2 WO2009011520 A2 WO 2009011520A2 KR 2008004080 W KR2008004080 W KR 2008004080W WO 2009011520 A2 WO2009011520 A2 WO 2009011520A2
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Prior art keywords
calcium
nano
particles containing
source material
solvent
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PCT/KR2008/004080
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French (fr)
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WO2009011520A3 (en
Inventor
Jin Seong Jeon
Hye Seung Lee
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Naraentec Co., Ltd.
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Publication of WO2009011520A2 publication Critical patent/WO2009011520A2/en
Publication of WO2009011520A3 publication Critical patent/WO2009011520A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof

Definitions

  • the present invention relates to nano-particles containing calcium which show an excellent absorption rate compared with conventional calcium formulations, have high purity and uniform nano-structure, and can be produced easily in large scale without using expensive devices; and a method for preparing the same.
  • Calcium is one of the most abundant minerals in human body and an essential element. About 2 % of total body weight is calcium, and about 99 % of calcium in human body is contained in bone. Calcium takes important roles in forming and maintaining bones and teeth, and in many parts of enzyme activities in human body. Calcium is also involved with muscle contraction, release of neurotransmitter, control of heartbeat, blood coagulation, etc.
  • the deficiency of calcium can lead to rachitis. Since rachitis can cause malformation of bone and depression of development and growth, it is very important for juveniles to take calcium in constant level. In case of adults, the deficiency of calcium can cause osteomalacia, and low calcium level in blood can cause muscular stiffness and leg cramp. Also, the deficiency of calcium can be a cause of hypertension, osteoporosis and colon cancer.
  • the osteoporosis is literally a disease of pore formation in bone. More than twenty million peoples in USA are suffering from the osteoporosis.
  • Osteoporosis can be caused by various factors such as excessive loss of bone material and in various types. Among them, the most common one is a postmenopausal osteoporosis in women. It has been known that about a quarter of women after menopause are taken with the osteoporosis. Usually, the largest loss of bone material occurs in vertebra, hip bone and rib, but in severe cases, the entire skeleton may be affected by the postmenopausal osteoporosis.
  • anchovy taken by the present manner shows very low absorption such that only 1 % of calcium ingredients contained in anchovy can be absorbed into the body.
  • the conventional calcium supplements as described above have been effective only to delay the development of osteoporosis, and could not have treated the osteoporosis completely.
  • calcium carbonate As a main ingredient.
  • the ratio of ionization by reacting with gastric juice is about 20 % when taken by general people, and about 4 % when taken by patients with low secretion of gastric juice.
  • calcium carbonate should become an easily disintegrable state and then react with gastric juice.
  • calcium carbonate has a high melting point (825 ° C) and is poorly soluble in water at normal temperature, and thus is not easy to ionize.
  • the size is prepared in nanometer scale, the absorption rate into human body can be increased since the surface area is maximized according to the characteristics of nano-materials and so the ionization rate is increased. Therefore, there have been many researches to prepare nano-calcium which has particle size of nanometer scale.
  • Korean Patent Laid-open Publication No. 10-2006-0091675 discloses a method for preparing nano-calcium having a nanoscale particle size by crushing shells of abalone or oyster.
  • the product contains impurities such as Fe 2 O 3 , Al 2 O 3 , MgO, SiO 2 , Pb, As, Ba, Mg, alkaline salt, etc. in addition to calcium ingredients.
  • impurities such as Fe 2 O 3 , Al 2 O 3 , MgO, SiO 2 , Pb, As, Ba, Mg, alkaline salt, etc.
  • the nano-calcium prepared by the disclosed method has a nano-sized spherical form of nano-particle. Such particles are likely to coagulate with each other to lower the surface energy, and so it is hard to expect any outstanding improvement in absorption rate according to the nano-particle preparation.
  • the object of the present invention is to provide nano-particles containing calcium which have a controlled size in nanometer scale, e.g., 1 ⁇ m, preferably from 1 ran to 900 nm, cause no coagulation, and can be produced easily in large scale by simplified process; and a method for preparing the same.
  • a method for preparing nano-particles containing calcium characterized in adding a polysaccharide compound to a mixture solution of a calcium source material and a solvent, is provided.
  • the nano-particles containing calcium of the present invention are prepared by a method comprising the steps of: (1) dissolving a calcium source material in a solvent, (2) adding a polysaccharide compound to the solution obtained by the step (1) and stirring the resulting mixture, and (3) separating and purifying nano-particles containing calcium from the mixture obtained by the step (2).
  • the calcium source material there is no special limitation to the calcium source material. Any calcium compound suitable as functional foods or raw materials for medical use is preferably used. Concretely, a material selected from the group consisting of calcium citrate, calcium gluconate, calcium hydroxide, calcium chloride, calcium nitrate, calcium lactate, calcium phosphate tribasic, calcium phosphate dibasic, calcium phosphate monobasic, calcium carbonate, calcium pantothenate, calcium propionate, calcium sulfate, calcium glycerophosphate, calcium oxide, calcium ascorbate, calcium alginate, calcium acetate, calcium sorbate, shell-derived calcium material, seaweed calcium, and combinations thereof can be used as the calcium source material.
  • the solvent there is no special limitation to the solvent as long as it can dissolve the calcium source material as above at normal or elevated temperature.
  • Any solvent suitable for preparing functional foods or raw materials for medical use is preferably used.
  • a solvent selected from the group consisting of water, lower alcohol (e.g. C1-C6 alcohol such as methanol, ethanol, propanol, etc.), acetone, aqueous acetic acid solution and combinations thereof can be used.
  • polysaccharide compound there is no special limitation to the polysaccharide compound. Any natural or synthetic polysaccharide compound can be used.
  • a polysaccharide compound selected from the group consisting of starch, chitin, chitosan, alginic acid, carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and combinations thereof can be used.
  • the nano-particle containing calcium prepared by the method according to the present invention preferably has particle diameter of 1 ⁇ m or less, and more preferably, from 1 nm to 900 nm.
  • the present invention mass-production of nano-particles containing calcium is possible by chemical synthesis process using raw materials which are harmless to human body.
  • the prepared nano-particle containing calcium has a particle size controlled to nanometer level, high absorption rate and high purity, and can be adjusted so as not to undergo absorption/digestion procedure in stomach, when administered in human body.
  • the method for preparing nano-particles containing calcium of the present invention can perform mass production by a simple process without using expensive devices, and thus can provide nano-calcium products with reasonable price.
  • Figure 1 is a photograph of the resulting product prepared in Example 1.
  • Figure 2 is a Field Emission Scanning Electron Microscope (FE-SEM) photograph of the nano-particles containing calcium prepared in Example 1.
  • FE-SEM Field Emission Scanning Electron Microscope
  • Figure 3 is a FE-SEM photograph (magnification: 1,000 times) of a nano-calcium supplementary product from oyster shells which is commercially available from CVS pharmacy in USA.
  • Figure 4 is a FE-SEM photograph (magnification: 20,000 times) of a crushed type nano- calcium from oyster shells which is commercially available in Korea.
  • Figure 5 is a FE-SEM photograph (magnification: 1,000 times) of a calcium supplementary product which is commercially available in Korea.
  • Figure 6 is photographs showing the state after dissolution in water for conventional nano-calcium product prepared by crushing method: (a) for side view and (b) for front view.
  • Figure 7 is photographs showing the state after dissolution in water for the nano-particles containing calcium prepared in Example 1 : (a) for side view and (b) for front view.
  • Figure 8 is an Energy-dispersive X-ray spectroscopy (EDX) analysis spectrum for the nano-particles containing calcium prepared in Example 1.
  • EDX Energy-dispersive X-ray spectroscopy
  • Step (1) The step for dissolving calcium source material
  • the calcium source material is added to a solvent and if necessary, heated and stirred to complete the dissolution.
  • the calcium source material there is no special limitation to the calcium source material. Any calcium compound suitable as functional foods or raw materials for medical use is preferably used. More preferably, a raw material whose safety is approved by the Food and Drug Administration (FDA) is used. Concretely, a material selected from the group consisting of calcium citrate, calcium gluconate, calcium hydroxide, calcium chloride, calcium nitrate, calcium lactate, calcium phosphate tribasic, calcium phosphate dibasic, calcium phosphate monobasic, calcium carbonate, calcium pantothenate, calcium propionate, calcium sulfate, calcium glycerophosphate, calcium oxide, calcium ascorbate, calcium alginate, calcium acetate, calcium sorbate, shell-derived calcium material, seaweed calcium, and combinations thereof can be used as the calcium source material.
  • FDA Food and Drug Administration
  • the solvent there is no special limitation to the solvent as long as it can dissolve the calcium source material as above.
  • Any solvent suitable for preparing functional foods or raw materials for medical use is preferably used.
  • a solvent selected from the group consisting of water, lower alcohol (e.g. C1-C6 alcohol such as methanol, ethanol, propanol, etc.), acetone, aqueous acetic acid solution and combinations thereof can be used. Water is preferably used in terms of its harmlessness to human body.
  • the amount of the calcium source material to be used can be selected appropriately in consideration of its solubility in the selected solvent. For example, when water is used as the solvent, it is preferable to determine the concentration of the calcium source material in a range of 0.001 M to 0.5 M, but not limited thereto. Only, if the amount of the calcium source material is too small, productivity and efficiency of the process may be lowered, whereas if the amount of the calcium source material is too large, nano- particles may not be formed effectively.
  • the temperature condition during the dissolution of the calcium source material there is no special limitation to the temperature condition during the dissolution of the calcium source material. Accordingly, the calcium source material may be dissolved in the solvent even at normal temperature (i.e. room temperature). But, for the complete and rapid dissolution, heating is preferred. There is no special limitation to the temperature condition of heating. For example, in a range of 25 to 150 ° C, preferably 90 to 110 ° C , the temperature to be raised can be selected appropriately in consideration of the boiling point of the solvent.
  • the dissolution of the calcium source material may be conducted for 0.5 to 24 hours, but not limited thereto.
  • reaction 1 For calcium carbonate, the following reaction 1 occurs:
  • Step (2) The step for adding polysaccharide compound To the solution of the calcium source material obtained by the step (1), a polysaccharide compound is added and the resulting mixture is stirred to form nano-particles containing calcium. It is understood that if a polysaccharide compound is added to a solution containing ionized calcium, the polysaccharide compound forms an ionic bond with the calcium ion, thereby forming a kind of complex structure.
  • the amount of the polysaccharide compound to be used there is no special limitation to the amount of the polysaccharide compound to be used. In consideration of the solubility of the polysaccharide compound to the solvent, it can be used in amount of 50 parts by weight or less, to 100 parts by weight of the solvent. Also, it is preferable to select the amount appropriately in a range of 0.01 to 10 moles per one mole of the calcium source material contained in the solution. If the concentration of the polysaccharide compound is lower than the level described above, the calcium- containing particle may grow too bigger, whereas if the concentration is higher than the level described above, the purity and content of the nano-particles containing calcium may decrease due to the excessive use of polysaccharide compound.
  • Any natural or synthetic polysaccharide compound can be used.
  • Polysaccharide compound which is non-toxic and harmless to human body is preferred.
  • a polysaccharide compound selected from the group consisting of starch, chitin, chitosan, alginic acid, carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and combinations thereof can be used.
  • the temperature condition during the addition and stirring of the polysaccharide compound there is no special limitation to the temperature condition during the addition and stirring of the polysaccharide compound.
  • the temperature can be selected appropriately in consideration of the boiling point of the solvent and the kind of the polysaccharide compound, etc.
  • the addition and stirring of the polysaccharide compound may be conducted for 0.5 to 24 hours, but not limited thereto.
  • Step (3) The step for separating and purifying nano-particles containing calcium Separation procedure is conducted to selectively recover nano-particles containing calcium from the mixture obtained by the step (2), and purification procedure is conducted to raise the purity of the product.
  • separation and purification methods There is no special limitation to the separation and purification methods. Any conventional techniques and apparatus known in this field for separation and purification can be used properly with or without further modification.
  • the separation and purification can be conducted by filtration method, adsorption method, electrophoresis method, reverse osmosis method, precipitation method, combinations thereof or the like. In terms of mass production, the separation using micro-filter is preferred.
  • the method for preparing nano-particles containing calcium of the present invention may use further ingredient(s) and/or comprise further step(s) as long as the purpose of the present invention can be achieved.
  • the nano-particle containing calcium prepared by the method according to the present invention preferably has particle diameter of 1 jam or less, and more preferably, from 1 nm to 900 nm.
  • the nano-particle containing calcium of the present invention does not coagulate and so has advantages of easy ionization in solution and good absorption in body. Therefore, it can be effectively used for the treatment and prevention of various diseases due to calcium deficiency such as osteoporosis, rachitis, osteomalacia, hypertension and colon cancer.
  • the nano- particle containing calcium of the present invention can be used in supplementary food for health in various forms such as solid formulation or liquid drink. Further, because the nano-particles containing calcium of the present invention are transferred to blood directly to increase bone density and any excessive particles containing calcium are excreted out of the body by blood, there is no problem even if relatively larger amount is taken, compared with conventional calcium supplements.
  • a functional food for supplementing calcium which comprises the nano-particles containing calcium prepared according to the present invention.
  • the functional food for supplementing calcium which can be provided by the present invention is characterized in comprising the nano-particles containing calcium prepared according to the present invention as main functional ingredient, and may further comprise various additives conventionally used in functional food such as excipient or the like.
  • the functional food for supplementing calcium of the present invention can be prepared in conventional forms for functional foods such as tablet, capsule, suspension, etc. There is no special limitation to the preparation method thereof.
  • Calcium pantothenate was dissolved in water with a concentration of 25 niM, and the solution was heated to 90 ° C and maintained for 10 minutes. Chitosan was added thereto with a concentration of 12.5 mM, and stirred uniformly at the same temperature for 2 hours.
  • Figure 1 is the photograph of the product.
  • FIG. 1 is the Field Emission Scanning Electron Microscope (FE-SEM) photograph of the nano-particles containing calcium prepared in Example 1.
  • the nano-particles prepared according to the present invention had substantially no coagulation, and the particle size thereof was in nanometer scale, i.e. as small as 1 nm to 900 nm in diameter.
  • Nano-particles containing calcium were prepared in the same manner as described in Example 1, except that calcium gluconate was used as the calcium source material.
  • the obtained nano-particles containing calcium were in a form of white fine powder.
  • FE-SEM FE-SEM, it was confirmed that nano-particles having diameter of about 1 nm to 900 nm were obtained, as in Example 1.
  • Nano-particles containing calcium were prepared in the same manner as described in Example 1, except that starch was used as the polysaccharide compound.
  • the obtained nano-particles containing calcium were in a form of white fine powder.
  • FE-SEM FE-SEM, it was confirmed that nano-particles having diameter of about 1 nm to 900 nm were obtained, as in Example 1.
  • Nano-particles containing calcium were prepared in the same manner as described in
  • Example 1 except that carboxymethylcellulose was used as the polysaccharide compound.
  • the obtained nano-particles containing calcium were in a form of white fine powder.
  • FE-SEM FE-SEM, it was confirmed that nano- particles having diameter of about 1 run to 900 nm were obtained, as in Example 1.
  • Figure 3 is the FE-SEM photograph (magnification: 1,000 times) of a nano-calcium supplementary product from oyster shells which is commercially available from CVS pharmacy in USA.
  • Figure 4 is the FE-SEM photograph (magnification: 20,000 times) of a crushed type nano-calcium from oyster shells which is commercially available in Korea.
  • Figure 5 is the FE-SEM photograph (magnification: 1,000 times) of a calcium supplementary product which is also commercially available in Korea.
  • the commercially available nano-calcium products which are currently on sale commonly have a problem of serious coagulation.
  • FIG. 6 is photographs showing the state after dissolution in water for conventional nano-calcium product prepared by crushing method: (a) for side view and (b) for front view.
  • Figure 7 is photographs showing the state after dissolution in water for the nano- particles containing calcium prepared in Example 1 : (a) for side view and (b) for front view.
  • the conventional crushed type nano-calcium was almost not dissolved in water at room temperature since it had a large degree of coagulation.
  • the nano-particle containing calcium prepared by the present invention was dissolved immediately after the addition to water and formed a clear solution, which means that the nano-particle containing calcium prepared by the present invention has excellent solubility characteristics.
  • the nano-particles containing calcium prepared by chemical synthesis process according to the present invention can be controlled in particle size to nanometer level, and have advantages of high absorption rate and high purity, and can be economically produced in large scale without using expensive devices.

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Abstract

The present invention relates to nano-particles containing calcium which show an excellent absorption rate compared with conventional calcium formulations, have high purity and uniform nano-structure, and can be produced easily in large scale without using expensive devices; and a method for preparing the same.

Description

NANO-PARTICLES CONTAINING CALCIUM AND METHOD FOR PREPARING THE SAME
TECHNICAL FIELD The present invention relates to nano-particles containing calcium which show an excellent absorption rate compared with conventional calcium formulations, have high purity and uniform nano-structure, and can be produced easily in large scale without using expensive devices; and a method for preparing the same.
BACKGROUND ART
Calcium is one of the most abundant minerals in human body and an essential element. About 2 % of total body weight is calcium, and about 99 % of calcium in human body is contained in bone. Calcium takes important roles in forming and maintaining bones and teeth, and in many parts of enzyme activities in human body. Calcium is also involved with muscle contraction, release of neurotransmitter, control of heartbeat, blood coagulation, etc.
In case of children, the deficiency of calcium can lead to rachitis. Since rachitis can cause malformation of bone and depression of development and growth, it is very important for juveniles to take calcium in constant level. In case of adults, the deficiency of calcium can cause osteomalacia, and low calcium level in blood can cause muscular stiffness and leg cramp. Also, the deficiency of calcium can be a cause of hypertension, osteoporosis and colon cancer.
In particular, the osteoporosis is literally a disease of pore formation in bone. More than twenty million peoples in USA are suffering from the osteoporosis.
Generally, both men and women experience a decrease of bone mass when they are over forty. But, women are still more vulnerable to the osteoporosis. Osteoporosis can be caused by various factors such as excessive loss of bone material and in various types. Among them, the most common one is a postmenopausal osteoporosis in women. It has been known that about a quarter of women after menopause are taken with the osteoporosis. Usually, the largest loss of bone material occurs in vertebra, hip bone and rib, but in severe cases, the entire skeleton may be affected by the postmenopausal osteoporosis.
Because bones in human body have to endure heavy weight, they are sensitive to pain, malformation and fracture. As a direct result of the osteoporosis, at least fifteen million cases of bone fracture occur annually, among which about 2 % falls on the fracture of hip bone that is a terrible fracture to the patients. 12 to 20 % of the fracture of hip bone is seriously fatal, and a half of the survivors should be under long-term care in hospital. A third of women and a sixth of men will experience the fracture of hip bone. Conventionally, ionized calcium solution, calcium product from oyster shell, animal bone, milk, anchovy or the like have been usually taken to treat the osteoporosis.
However, when the ionized calcium is taken to increase bone density, the problem of co- adsorbing heavy metal in body onto the bone may be caused. The animal bone may cause a calculus formation in body. Also, anchovy taken by the present manner shows very low absorption such that only 1 % of calcium ingredients contained in anchovy can be absorbed into the body. The conventional calcium supplements as described above have been effective only to delay the development of osteoporosis, and could not have treated the osteoporosis completely.
To solve the problems, many researchers and companies have tried eagerly to develop a calcium supplementary product which has high purity, high absorption rate and easiness of ionization.
Most of commercially available calcium supplementary products at present contain calcium carbonate as a main ingredient. In case of such calcium supplementary product mainly containing calcium carbonate, it has been known that the ratio of ionization by reacting with gastric juice is about 20 % when taken by general people, and about 4 % when taken by patients with low secretion of gastric juice. To be ionized easily, calcium carbonate should become an easily disintegrable state and then react with gastric juice. However, calcium carbonate has a high melting point (825 °C) and is poorly soluble in water at normal temperature, and thus is not easy to ionize.
However, if the size is prepared in nanometer scale, the absorption rate into human body can be increased since the surface area is maximized according to the characteristics of nano-materials and so the ionization rate is increased. Therefore, there have been many researches to prepare nano-calcium which has particle size of nanometer scale.
As well known in nanotechnology field, when the particle size of a material becomes smaller than its Bohr radius, unexpected effects from sudden changes in physical- chemical properties may be found. Since the theoretical Bohr radius of calcium is 0.19 nm, the nano-calcium having particle size of tens - hundreds nanometer level does not have the problem of unexpected toxicity generation, and gives an advantage of great increase in absorption rate compared with common bulk-sized calcium.
Korean Patent Laid-open Publication No. 10-2006-0091675 (Title: Method for preparing nano-powder of oyster shell having increased absorption rate of calcium into body) discloses a method for preparing nano-calcium having a nanoscale particle size by crushing shells of abalone or oyster. However, as shown in the table of analysis to the nano-calcium prepared by the crushing method disclosed in the above publication, the product contains impurities such as Fe2O3, Al2O3, MgO, SiO2, Pb, As, Ba, Mg, alkaline salt, etc. in addition to calcium ingredients. This means that if the nano-calcium prepared by the disclosed method is taken for a long time, toxic arsenic (As) and heavy metal lead (Pb) may be accumulated in body with considerable amount, thereby causing fatal results to human.
Further, the nano-calcium prepared by the disclosed method has a nano-sized spherical form of nano-particle. Such particles are likely to coagulate with each other to lower the surface energy, and so it is hard to expect any outstanding improvement in absorption rate according to the nano-particle preparation.
DETAILED DESCRIPTION OF THE INVENTION
TECHNICAL PURPOSE
As a solution to the above-mentioned problems of prior arts, the object of the present invention is to provide nano-particles containing calcium which have a controlled size in nanometer scale, e.g., 1 μm, preferably from 1 ran to 900 nm, cause no coagulation, and can be produced easily in large scale by simplified process; and a method for preparing the same.
TECHNICAL SOLUTION
According to the present invention, a method for preparing nano-particles containing calcium, characterized in adding a polysaccharide compound to a mixture solution of a calcium source material and a solvent, is provided.
According to one embodiment of the present invention, the nano-particles containing calcium of the present invention are prepared by a method comprising the steps of: (1) dissolving a calcium source material in a solvent, (2) adding a polysaccharide compound to the solution obtained by the step (1) and stirring the resulting mixture, and (3) separating and purifying nano-particles containing calcium from the mixture obtained by the step (2).
hi the present invention, there is no special limitation to the calcium source material. Any calcium compound suitable as functional foods or raw materials for medical use is preferably used. Concretely, a material selected from the group consisting of calcium citrate, calcium gluconate, calcium hydroxide, calcium chloride, calcium nitrate, calcium lactate, calcium phosphate tribasic, calcium phosphate dibasic, calcium phosphate monobasic, calcium carbonate, calcium pantothenate, calcium propionate, calcium sulfate, calcium glycerophosphate, calcium oxide, calcium ascorbate, calcium alginate, calcium acetate, calcium sorbate, shell-derived calcium material, seaweed calcium, and combinations thereof can be used as the calcium source material.
In the present invention, there is no special limitation to the solvent as long as it can dissolve the calcium source material as above at normal or elevated temperature. Any solvent suitable for preparing functional foods or raw materials for medical use is preferably used. Concretely, a solvent selected from the group consisting of water, lower alcohol (e.g. C1-C6 alcohol such as methanol, ethanol, propanol, etc.), acetone, aqueous acetic acid solution and combinations thereof can be used.
In the present invention, there is no special limitation to the polysaccharide compound. Any natural or synthetic polysaccharide compound can be used. Preferably, a polysaccharide compound selected from the group consisting of starch, chitin, chitosan, alginic acid, carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and combinations thereof can be used.
The nano-particle containing calcium prepared by the method according to the present invention preferably has particle diameter of 1 μm or less, and more preferably, from 1 nm to 900 nm.
ADVANTAGEOUS EFFECTS
According to the present invention, mass-production of nano-particles containing calcium is possible by chemical synthesis process using raw materials which are harmless to human body. The prepared nano-particle containing calcium has a particle size controlled to nanometer level, high absorption rate and high purity, and can be adjusted so as not to undergo absorption/digestion procedure in stomach, when administered in human body. Differently from conventional nano-calcium production technologies, the method for preparing nano-particles containing calcium of the present invention can perform mass production by a simple process without using expensive devices, and thus can provide nano-calcium products with reasonable price.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photograph of the resulting product prepared in Example 1.
Figure 2 is a Field Emission Scanning Electron Microscope (FE-SEM) photograph of the nano-particles containing calcium prepared in Example 1.
Figure 3 is a FE-SEM photograph (magnification: 1,000 times) of a nano-calcium supplementary product from oyster shells which is commercially available from CVS pharmacy in USA.
Figure 4 is a FE-SEM photograph (magnification: 20,000 times) of a crushed type nano- calcium from oyster shells which is commercially available in Korea.
Figure 5 is a FE-SEM photograph (magnification: 1,000 times) of a calcium supplementary product which is commercially available in Korea.
Figure 6 is photographs showing the state after dissolution in water for conventional nano-calcium product prepared by crushing method: (a) for side view and (b) for front view.
Figure 7 is photographs showing the state after dissolution in water for the nano-particles containing calcium prepared in Example 1 : (a) for side view and (b) for front view.
Figure 8 is an Energy-dispersive X-ray spectroscopy (EDX) analysis spectrum for the nano-particles containing calcium prepared in Example 1.
EMBODIMENT TO CARRY OUT THE INVENTION
The method for preparing nano-particles containing calcium of the present invention is explained step by step in detail below.
Step (1); The step for dissolving calcium source material
The calcium source material is added to a solvent and if necessary, heated and stirred to complete the dissolution.
There is no special limitation to the calcium source material. Any calcium compound suitable as functional foods or raw materials for medical use is preferably used. More preferably, a raw material whose safety is approved by the Food and Drug Administration (FDA) is used. Concretely, a material selected from the group consisting of calcium citrate, calcium gluconate, calcium hydroxide, calcium chloride, calcium nitrate, calcium lactate, calcium phosphate tribasic, calcium phosphate dibasic, calcium phosphate monobasic, calcium carbonate, calcium pantothenate, calcium propionate, calcium sulfate, calcium glycerophosphate, calcium oxide, calcium ascorbate, calcium alginate, calcium acetate, calcium sorbate, shell-derived calcium material, seaweed calcium, and combinations thereof can be used as the calcium source material.
There is no special limitation to the solvent as long as it can dissolve the calcium source material as above. Any solvent suitable for preparing functional foods or raw materials for medical use is preferably used. Concretely, a solvent selected from the group consisting of water, lower alcohol (e.g. C1-C6 alcohol such as methanol, ethanol, propanol, etc.), acetone, aqueous acetic acid solution and combinations thereof can be used. Water is preferably used in terms of its harmlessness to human body.
The amount of the calcium source material to be used can be selected appropriately in consideration of its solubility in the selected solvent. For example, when water is used as the solvent, it is preferable to determine the concentration of the calcium source material in a range of 0.001 M to 0.5 M, but not limited thereto. Only, if the amount of the calcium source material is too small, productivity and efficiency of the process may be lowered, whereas if the amount of the calcium source material is too large, nano- particles may not be formed effectively.
There is no special limitation to the temperature condition during the dissolution of the calcium source material. Accordingly, the calcium source material may be dissolved in the solvent even at normal temperature (i.e. room temperature). But, for the complete and rapid dissolution, heating is preferred. There is no special limitation to the temperature condition of heating. For example, in a range of 25 to 150 °C, preferably 90 to 110 °C , the temperature to be raised can be selected appropriately in consideration of the boiling point of the solvent. The dissolution of the calcium source material may be conducted for 0.5 to 24 hours, but not limited thereto.
During the dissolution of the calcium source material, various reactions may occur in the solution according to the kind of raw material. As one example, for calcium carbonate, the following reaction 1 occurs:
[Reaction 1]
CaCO3(S) + 2H+(aq) → Ca2+(aq) + CO2(g) t + H2O
As shown in the above reaction 1, when calcium carbonate is used as raw material, it is dissolved and ionized in water to generate calcium ion, carbon dioxide and water. The carbon dioxide generated as gas is discharged from the reactor.
Step (2): The step for adding polysaccharide compound To the solution of the calcium source material obtained by the step (1), a polysaccharide compound is added and the resulting mixture is stirred to form nano-particles containing calcium. It is understood that if a polysaccharide compound is added to a solution containing ionized calcium, the polysaccharide compound forms an ionic bond with the calcium ion, thereby forming a kind of complex structure.
There is no special limitation to the amount of the polysaccharide compound to be used. In consideration of the solubility of the polysaccharide compound to the solvent, it can be used in amount of 50 parts by weight or less, to 100 parts by weight of the solvent. Also, it is preferable to select the amount appropriately in a range of 0.01 to 10 moles per one mole of the calcium source material contained in the solution. If the concentration of the polysaccharide compound is lower than the level described above, the calcium- containing particle may grow too bigger, whereas if the concentration is higher than the level described above, the purity and content of the nano-particles containing calcium may decrease due to the excessive use of polysaccharide compound.
Any natural or synthetic polysaccharide compound can be used. Polysaccharide compound which is non-toxic and harmless to human body is preferred. Concretely, a polysaccharide compound selected from the group consisting of starch, chitin, chitosan, alginic acid, carboxymethylcellulose (CMC), hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and combinations thereof can be used.
There is no special limitation to the temperature condition during the addition and stirring of the polysaccharide compound. For example, in a range of 25 to 150 °C, preferably 90 to 110 °C, the temperature can be selected appropriately in consideration of the boiling point of the solvent and the kind of the polysaccharide compound, etc. The addition and stirring of the polysaccharide compound may be conducted for 0.5 to 24 hours, but not limited thereto.
Step (3): The step for separating and purifying nano-particles containing calcium Separation procedure is conducted to selectively recover nano-particles containing calcium from the mixture obtained by the step (2), and purification procedure is conducted to raise the purity of the product.
There is no special limitation to the separation and purification methods. Any conventional techniques and apparatus known in this field for separation and purification can be used properly with or without further modification. For example, the separation and purification can be conducted by filtration method, adsorption method, electrophoresis method, reverse osmosis method, precipitation method, combinations thereof or the like. In terms of mass production, the separation using micro-filter is preferred.
In addition to the ingredients and/or steps as explained above, the method for preparing nano-particles containing calcium of the present invention may use further ingredient(s) and/or comprise further step(s) as long as the purpose of the present invention can be achieved.
The nano-particle containing calcium prepared by the method according to the present invention preferably has particle diameter of 1 jam or less, and more preferably, from 1 nm to 900 nm.
Contrary to the micro-calcium particle which is prepared by conventional crushing method, etc. and has the problem of coagulation, the nano-particle containing calcium of the present invention does not coagulate and so has advantages of easy ionization in solution and good absorption in body. Therefore, it can be effectively used for the treatment and prevention of various diseases due to calcium deficiency such as osteoporosis, rachitis, osteomalacia, hypertension and colon cancer. Also, the nano- particle containing calcium of the present invention can be used in supplementary food for health in various forms such as solid formulation or liquid drink. Further, because the nano-particles containing calcium of the present invention are transferred to blood directly to increase bone density and any excessive particles containing calcium are excreted out of the body by blood, there is no problem even if relatively larger amount is taken, compared with conventional calcium supplements.
Therefore, according to another aspect of the present invention, a functional food for supplementing calcium, which comprises the nano-particles containing calcium prepared according to the present invention, is provided. The functional food for supplementing calcium which can be provided by the present invention is characterized in comprising the nano-particles containing calcium prepared according to the present invention as main functional ingredient, and may further comprise various additives conventionally used in functional food such as excipient or the like. Also, the functional food for supplementing calcium of the present invention can be prepared in conventional forms for functional foods such as tablet, capsule, suspension, etc. There is no special limitation to the preparation method thereof.
The present invention will be more specifically explained by the following examples. However, it should be understood that the following examples are intended to illustrate the present invention, and cannot limit the scope of the present invention in any manner. [EXAMPLES] Example 1
Calcium pantothenate was dissolved in water with a concentration of 25 niM, and the solution was heated to 90 °C and maintained for 10 minutes. Chitosan was added thereto with a concentration of 12.5 mM, and stirred uniformly at the same temperature for 2 hours.
The resulting mixture was separated by using a micro-filter, and dried to obtain nano- particles containing calcium in a form of white fine powder. Figure 1 is the photograph of the product.
To the obtained nano-particles containing calcium, a photograph to observe the particle morphology was taken by using a Field Emission Scanning Electron Microscope (FE- SEM). Figure 2 is the Field Emission Scanning Electron Microscope (FE-SEM) photograph of the nano-particles containing calcium prepared in Example 1. As shown in Figure 2, the nano-particles prepared according to the present invention had substantially no coagulation, and the particle size thereof was in nanometer scale, i.e. as small as 1 nm to 900 nm in diameter.
Also, an analysis to the obtained nano-particles containing calcium was conducted by using EDX (Energy-dispersive X-ray spectroscopy). The resulting spectrum is shown in Figure 8.
Example 2
Nano-particles containing calcium were prepared in the same manner as described in Example 1, except that calcium gluconate was used as the calcium source material. The obtained nano-particles containing calcium were in a form of white fine powder. As a result of observation with FE-SEM, it was confirmed that nano-particles having diameter of about 1 nm to 900 nm were obtained, as in Example 1.
Example 3
Nano-particles containing calcium were prepared in the same manner as described in Example 1, except that starch was used as the polysaccharide compound. The obtained nano-particles containing calcium were in a form of white fine powder. As a result of observation with FE-SEM, it was confirmed that nano-particles having diameter of about 1 nm to 900 nm were obtained, as in Example 1.
Example 4
Nano-particles containing calcium were prepared in the same manner as described in
Example 1, except that carboxymethylcellulose was used as the polysaccharide compound. The obtained nano-particles containing calcium were in a form of white fine powder. As a result of observation with FE-SEM, it was confirmed that nano- particles having diameter of about 1 run to 900 nm were obtained, as in Example 1.
Comparative Example 1
For the comparison with the nano-particles containing calcium obtained in Example 1, photographs to observe the particle morphology of commercially available nano-calcium products were taken by using FE-SEM. Figures 3 to 5 are the resulting photographs.
Figure 3 is the FE-SEM photograph (magnification: 1,000 times) of a nano-calcium supplementary product from oyster shells which is commercially available from CVS pharmacy in USA. Figure 4 is the FE-SEM photograph (magnification: 20,000 times) of a crushed type nano-calcium from oyster shells which is commercially available in Korea. Figure 5 is the FE-SEM photograph (magnification: 1,000 times) of a calcium supplementary product which is also commercially available in Korea. As shown in Figures 3 to 5, the commercially available nano-calcium products which are currently on sale, commonly have a problem of serious coagulation.
Comparative Example 2
For the comparison of the solubility characteristics of nano-calcium particles in aqueous solution, 0.2 g of the nano-particles containing calcium obtained in Example 1 and 0.2 g of the commercially available nano-calcium (crushed type) were respectively dissolved in 100 ml of water at room temperature. Figure 6 is photographs showing the state after dissolution in water for conventional nano-calcium product prepared by crushing method: (a) for side view and (b) for front view. Figure 7 is photographs showing the state after dissolution in water for the nano- particles containing calcium prepared in Example 1 : (a) for side view and (b) for front view.
As shown in Figure 6, the conventional crushed type nano-calcium was almost not dissolved in water at room temperature since it had a large degree of coagulation. However, as shown in Figure 7, the nano-particle containing calcium prepared by the present invention was dissolved immediately after the addition to water and formed a clear solution, which means that the nano-particle containing calcium prepared by the present invention has excellent solubility characteristics.
INDUSTRIAL APPLICABILITY
As explained above in detail, the nano-particles containing calcium prepared by chemical synthesis process according to the present invention can be controlled in particle size to nanometer level, and have advantages of high absorption rate and high purity, and can be economically produced in large scale without using expensive devices. Thus, according to the present invention, it is possible to provide nano-calcium products with reasonable price.

Claims

1. A method for preparing nano-particles containing calcium, characterized in adding a polysaccharide compound to a mixture solution of a calcium source material and a solvent.
2. The method according to claim 1, wherein the method comprises the steps of:
(1) dissolving a calcium source material in a solvent,
(2) adding a polysaccharide compound to the solution obtained by the step (1) and stirring the resulting mixture, and (3) separating and purifying nano-particles containing calcium from the mixture obtained by the step (2).
3. The method according to claim 1, wherein the calcium source material is selected from the group consisting of calcium citrate, calcium gluconate, calcium hydroxide, calcium chloride, calcium nitrate, calcium lactate, calcium phosphate tribasic, calcium phosphate dibasic, calcium phosphate monobasic, calcium carbonate, calcium pantothenate, calcium propionate, calcium sulfate, calcium glycerophosphate, calcium oxide, calcium ascorbate, calcium alginate, calcium acetate, calcium sorbate, shell- derived calcium material, seaweed calcium, and combinations thereof.
4. The method according to claim 1, wherein the solvent is selected from the group consisting of water, lower alcohol, acetone, aqueous acetic acid solution, and combinations thereof.
5. The method according to claim 1, wherein the polysaccharide compound is selected from the group consisting of starch, chitin, chitosan, alginic acid, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and combinations thereof.
6. The method according to claim 2, wherein in the step (1), the calcium source material is dissolved in the solvent at 25 °C to 150 °C .
7. The method according to claim 2, wherein in the step (2), the polysaccharide compound is added and stirred at 25 °C to 150 °C .
8. The method according to claim 2, wherein in the step (3), the nano-particles containing calcium is separated and purified by a method selected from the group consisting of filtration method, adsorption method, electrophoresis method, reverse osmosis method, precipitation method, and combinations thereof.
9. A nano-particle containing calcium, which is prepared by the method according to any one of claims 1 to 8 and has particle diameter of 1 p or less.
10. The nano-particle containing calcium according to claim 9, which has particle diameter of 1 nm to 900 nm.
11. A functional food for supplementing calcium, which comprises the nano- particles containing calcium prepared by the method according to any one of claims 1 to 8.
PCT/KR2008/004080 2007-07-13 2008-07-11 Nano-particles containing calcium and method for preparing the same WO2009011520A2 (en)

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KR200481994Y1 (en) 2016-04-04 2016-12-05 김성필 Bar type float for sea fishing

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