JP3482242B2 - Fine particles enclosing a physiologically active substance and a method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a physically or chemically unstable substance and a substance having an offensive odor or bitterness, particularly a substance having such properties, which is used as a main component of a medicine or a so-called "health food". The present invention relates to fine particles encapsulated in a relatively stable shell and a method for producing the same in order to stably store a physiologically active substance used as "," not easily processed, and easily administered orally. The fine particles according to the present invention can be used as a raw material for the production of pharmaceuticals and processed foods, depending on the physiologically active substance to be encapsulated. Since the outer shell of the fine particles according to the present invention contains calcium as a main component, it is also useful for supplementing calcium.

[0002]

2. Description of the Related Art Drugs and so-called "health foods", a group of foods, such as extracted / refined foods from natural products, are physically / chemically unstable, have a bitterness or offensive odor, orally When administered or ingested, there are some that have low absorbability or that are easily decomposed in the stomach. As a method of stabilizing the above-mentioned drugs during storage or in the digestive tract, and facilitating oral administration of drugs or health foods having bitterness or off-flavor, encapsulation in capsules, blending of flavoring / flavoring agents, various Other measures such as applying coatings (sugar coating, enteric coating, etc.) have been adopted. Capsules, coated tablets, and the like are relatively large in size and therefore have a difficulty in being taken by some humans, have low absorbability, and cannot be further used as a material for processed foods. In recent years, the importance of fish oil has been reassessed, and as a result of research in various fields, ω-3 acids contained in fish oil, especially highly unsaturated fatty acids such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), etc. Has been found to contribute significantly to blood physiology, metabolism, and other functions, and also has various effects on the brain, such as memory-enhancing effects, and thus prevention of Alzheimer-type dementia, which has been observed to increase in recent years. It is considered to be used for such purposes. For example, a DHA-containing oil directly encapsulated in a soft capsule, or a hard capsule encapsulated with dextrin, etc., is commercially available as a “health food,” but it has an offensive odor peculiar to fish oil. Since it has a large number of unsaturated groups in the molecule, it is easy to be oxidized, and when it is oxidized, it has a strong offensive odor. It is also known that Moreover, since this kind of health food is a capsule, there is a problem in that it has a strong image of a drug.

[0003]

SUMMARY OF THE INVENTION Therefore, the essential object of the present invention to be solved by the invention is to provide fine particles in which the above-mentioned physiologically active substance is encapsulated as a core substance and a method for producing the same. In order to solve the above-mentioned problems related to the prior art.

[0004] A specific object of the present invention is to provide fine particles in which a physiologically active substance is encapsulated in a micro shell which is different in material from soft capsules and hard capsules. The purpose of the present invention is to make it easy and to make it available as a raw material for processed foods, thereby enabling taking and ingesting physiologically active substances in a natural form.

Still another specific object of the present invention is to provide a particulate shell having acid resistance so that the encapsulated physiologically active substance flows out in the intestine rather than in the stomach (conventional D
Since HA capsules dissolve in the stomach, there was a defect in that an offensive odor comes out of the oral cavity due to "Okubi" or so-called "Gep", but this can be effectively prevented).

[0006]

MEANS TO SOLVE THE PROBLEM AND ACTION TO Achieve the Object As a result of intensive studies to achieve the above object, the present inventors have mixed an oily physiologically active substance with water to emulsify the emulsion If you stir things at high speed, the oil droplets behave as a kind of solid, and as a result of the relative motion with water, the zeta is on the surface of the oil droplets.
(ξ) An electric potential is generated and electrostatically charged, and while in this state,
By adding the solid fine particles that are smaller than the oil droplets and have an electric charge opposite to that of the oil droplet surface, the fine particles are adsorbed on the oil droplet surface. It was found that a physiologically active substance can be encapsulated, and the basic concept of the present invention was obtained. As an oil-based physiologically active substance as a core-forming substance, DHA and EPA-containing purified fish oil were first used successfully, and even if it was a water-soluble physiologically active substance, a surfactant (in consideration of use safety etc.) Lecithin, yogurt powder and the like) are preferably added, and then suspended in, for example, hydrogenated oil after coating with a sodium alginate solution, and then cooled to solidify into fine particles, which can be used as a core substance. It was also found that the substance can be used as a core substance by dispersing it in hardened oil or the like. Examples of other core substances include oily physiologically active substances such as β-carotene, antibiotics such as erythromycin and mitomycin, heme iron, germ oil, vitamins A and E and the like. As a result of repeated studies on solid fine particles that constitute the shell for encapsulating the core substance,
It was found that calcium particles are preferable in consideration of stability after shell formation, safety for human body, and the like. This is because calcium is a nutritional component that has been sought to be insufficiently taken in recent years, does not adversely affect the living body, and has low thermal conductivity, and protects the core substance from heat. In this case, as the calcium particles, it is possible to use bone powder of cattle or pork, fine powder of shells such as oysters and scallops, and inorganic calcium materials such as calcium carbonate. However, it was found that the calcium powder alone may break the electrostatic bond even if the shell is once formed. Therefore, as a result of further studies, for example, milk-calcium powder containing milk protein (for example, sodium hydroxide was added to the residual liquid obtained by recovering protein and lactose from the acidic whey produced during the production of Cheddar cheese). It is neutralized, the precipitate formed is separated and powdered, rich in minerals, especially calcium,
Milk protein also contains milk protein and is commercially available as “edible whey calcium powder” from Healthway Co., Ltd.) as solid fine particles, the milk protein has the ability to coordinate with calcium and fatty acids. Therefore, it was found that a stable shell can be formed. Incidentally, even if the bone powder, fine shell powder or inorganic calcium material described above is used together with milk protein such as casein or sodium alginate, a stable calcium shell can be formed (sodium alginate can be used in a short time. Since it binds to calcium by an ion exchange reaction and gels to function as a fixing agent, even a hydrophilic core substance can be stably encapsulated in the calcium shell without flowing out).

According to the present invention, the physiologically active substance-encapsulated calcium fine particles can be prepared in various modes. For example, it can be prepared by adding an oily physiologically active substance and milk / calcium powder to water and stirring the mixture at a high speed. Also, in an aqueous milk protein solution such as casein, the oily physiologically active substance and bone powder or inorganic calcium as a calcium source can be prepared. It can be prepared by adding and stirring at high speed. The stirring speed in these cases is 3000-10000 rpm and 6000-
Approximately 8,000 rpm is preferable, and a stirring time of about 10 minutes is sufficient. The calcium shell formed can be fixed by adding sodium alginate and stirring after high-speed stirring. The stirring in this case is a treatment for further strengthening by binding alginic acid to the calcium shell encapsulating the physiologically active substance already formed by the action of calcium fine powder and milk protein. The stirring condition is about 2000 rpm for about 5 minutes. Is enough. It is also possible to separately prepare a core-forming substance-containing emulsion and a shell-forming substance-containing suspension, combine these liquids, and perform high-speed stirring to prepare physiologically active substance-encapsulated calcium fine particles. In this case, when the physiologically active substance to be the core substance is an oily substance, an emulsion containing the core forming substance is prepared by adding it to water and stirring it, and when it is a hydrophilic substance, its fine powder. Is coated with a surfactant-containing sodium alginate solution and then suspended in oil, or added to heated hydrogenated oil and stirred to prepare a core-forming substance-containing dispersion liquid. On the other hand, milk-calcium or a calcium material powder as a shell-forming substance and milk protein are added to water, and stirring is preferably performed at high speed to obtain a suspension containing the shell-forming substance in which calcium fine particles are sufficiently dispersed in water. Prepare. The stirring speed is 3000-10000r
pm, preferably about 6000 rpm. Next, the shell-forming substance-containing suspension and the core-forming substance-containing emulsion or suspension described above are combined and stirred at high speed. The stirring speed in this case is also 3000-10000 rpm, but about 6000-8000 rpm is preferable. By the above operation, the calcium fine particles are electrostatically adsorbed on the surface of the oil droplets or the oil film (depending on the property of the selected physiologically active substance), and the milk protein has the ability to coordinate with oils and calcium. Since sodium alginate binds to calcium by an ion exchange reaction and gels, the physiologically active substance is in a state of being encapsulated in the shell of calcium fine particles. Therefore, after the above high-speed stirring, the solution is subjected to filtration or centrifugation, and then dried to obtain desired physiologically active substance-encapsulated calcium fine particles. Drying can be performed by any method known per se, for example, by adopting ventilation, vacuum, spraying, freeze-drying or the like, and if spray-drying, filtration and centrifugation operation are unnecessary. The diameter of the obtained fine particles is 3 mm or less (150-200 μm according to imaging measurement using an electron microscope, although the thickness of the calcium shell formed depends on the operating conditions), and it behaves as a powder. Therefore, it is easy to handle. Incidentally, by appropriately setting the operating conditions, it is possible to form a lump of a certain size in which the calcium-milk protein layer is used as a matrix and the core substance is enclosed.

In the obtained fine particles or small-sized lumps, the outer shell or matrix layer blocks invasion of air and leakage of offensive odor,
Furthermore, since calcium has a low thermal conductivity, it has the effect of preventing deterioration of the core substance (even if the outside temperature reaches 100 ° C when the core substance is refined fish oil containing DHA or EPA, the deterioration temperature of the fish oil is Therefore, it can be the final product, but it can also be provided with acid resistance.
That is, in the course of research on a sticking agent for forming a stable calcium shell, gelatin, carrageenan, glycomannan, duran gum, sodium alginate, and locust bean gum A sol was prepared by combining at least two selected substances. When the above-mentioned core substance-encapsulated calcium fine particles or agglomerates are coated with a gel and then crosslinked to form a gel, it has heat resistance (does not dissolve even at 100 ° C) and has excellent acid resistance (pH of gastric juice). 2.
It was found that it could be easily dissolved in a solution of about 0). Therefore, the core substance can be made to dissolve in the intestine rather than in the stomach. In this case, if the calcium layers having different thicknesses are prepared and appropriately mixed, it is possible to provide sustained release. . In this case, the formation of the acid resistant coating can be performed on the bioactive substance-encapsulated calcium fine particles, but it is also possible to form the acid resistant coating simultaneously with the formation of the calcium shell. You can reduce the number.

The heat-resistant and heat-resistant / acid-resistant fine particles or agglomerates according to the present invention can be used as a material for the production of various processed foods. For example, when refined fish oil is used as the core substance, ice cream, drink, etc. It can be used as a material for nutritional enhancement and calcium supplementation of agents, noodles, miso and the like or baked foods such as breads and biscuits.

[0010]

EXAMPLES The present invention will be described in more detail and concretely with reference to production examples and test examples. In the production examples below, DHA-containing purified fish oil, EPA-containing purified fish oil and β-carotene are representative examples of oily physiologically active substances, erythromycin is a representative example of antibiotics, and powdery physiologically active substances are representative examples. Heme iron was adopted as the core material.

Production Example 1 (Encapsulation of fish oil) 100 g of refined fish oil (containing 27% of DHA), 300 g of milk / calcium fine powder under 200 mesh ("Edible whey calcium powder" manufactured by Healthway Co., Ltd.), Add 1.0 liter of water to a beaker and 800 with a high speed homogenizer.
Stir for 10 minutes at 0 rpm. Then, 200 ml of 0.3% sodium alginate aqueous solution was added, and the mixture was stirred at 2000 rpm for 5 minutes. After that, use a spray drier to reduce the inlet temperature to 120
180 g of DHA-containing purified fish oil-encapsulated calcium microparticles was obtained by treating at below ℃. The particle size of these fine particles is about 17
It was 0 μm.

Test Example (Oven Stability Test) An oven stability test was carried out using the DHA-containing purified fish oil-encapsulated calcium fine particles obtained in Production Example 1 and DHA-containing powdery products commercially available from various companies as test products.
That is, each test product was placed in a petri dish, placed in a constant temperature bath (temperature 40 ° C, relative humidity 75%), and sampled over time during the 28-day test period to obtain a peroxide value ["peroxide value
(POV), meq / kg "] was measured. The results are shown in Figure 1, and only the purified fish oil encapsulated in the microparticles of the present invention had a peroxide value (POV) of 5 me over the entire test period.
It was less than q / kg and was found to be kept stable. By the way, the stability of fats and oils is expressed as the time until the peroxide value reaches a certain value (acid rancid point) .In general, in the case of animal fats and oils, the rancid point is the point at which the peroxide value reaches 20 meq / kg. It is said that.

The fine particles obtained in Production Example 1 were subjected to the same harsh oven stability test as above, but at 70 ° C., and the peroxide value of the fish oil encapsulated in the calcium shell was sampled over time to determine the peroxide value. The measured results are shown in Table 1 below.

[0014]

[Table 1]

Production Example 2 (encapsulation of fish oil) 180 g of beef bone powder finely divided to a particle size of about 1 μm, milk protein 180
g, gelatin 8.0g, κ-carrageenan 0.8g and water 1200
Add g to a 2 liter container and heat to 60
-6000 rpm with high speed homomixer after adjusting to 70 ℃
And stirred for 10 minutes. Next, refined fish oil (20% EPA
100 g) was added, and the mixture was stirred for 10 minutes at 8000 rpm with a high-speed homomixer while maintaining the liquid temperature at 60-70 ° C. The resulting emulsion is dried with a hot air blower at 50 ° C.
I gave it for 10 hours. The obtained lump was crushed and sieved to obtain 439 g of fine particles under 35 mesh.

Oven stability tests were carried out using the obtained purified fish oil-encapsulated fine particles and non-encapsulated refined fish oil as test products (conditions: 40 ° C., relative humidity 75%, 3%).
0 days). The results are shown in Table 2 below and the encapsulated refined fish oil showed a very slight increase in peroxide number over the entire test period.

[0017]

[Table 2]

Using the obtained purified fish oil-encapsulated fine particles and purified fish oil clathrated with dextran as a test product, a disintegration test was carried out using artificial gastric juice and intestinal fluid according to the Japanese Pharmacopoeia (the conditions were both 40 ° C., 10 minutes). The results are shown in Table 3 below.
The microparticles according to the present invention are hardly soluble in gastric juice and disintegrate in intestinal fluid, so that they obviously have an enteric tendency.

[0019]

[Table 3]

Production Example 3 (Encapsulation of β-carotene) Casein-Na (manufactured by Kishida Chemical Co., Ltd.) 15 g in 250 ml of water
And yogurt powder (manufactured by Morinaga Milk Industry Co., Ltd.) 2g was added and heated to prepare a casein-Na aqueous solution,
45 g of CaCO ₃ powder and β-carotene oil (β-
40 g of carotene (containing 30%) was added, and CaCO ₃ shells were formed on the β-carotene oil droplet surface by stirring with a high-speed homogenizer at 7,000 rpm for 10 minutes. A 0.3% aqueous solution (80 ml) of sodium alginate (manufactured by Kimitsu Chemical Co., Ltd.) was gradually added, followed by stirring at 3000 rpm for 5 minutes, followed by freeze-drying (drying conditions up to a product temperature of 40 ° C).
By doing so, about 100 g of reddish β-carotene-encapsulated calcium fine particles were obtained. The microparticles were allowed to stand under the condition of 70 ° C (24 hours) and observed over time, but no discoloration was observed, and it was revealed that β-carotene encapsulating calcium shell was protected from oxidation.

Production Example 4 (Encapsulation of Vitamin E) To 1077 g of oyster shell fine powder and 114 g of milk protein, 7317 g of water was added, which was previously stirred at 6000 rpm for 5 minutes, and then 520 g of vitamin E was added while heating. An emulsion was prepared by stirring at 8000 rpm for 10 minutes. The liquid temperature at this time was 67 ° C. On the other hand, 1.7 g of glucomannan, 15.5 g of carrageenan, 5.2 g of duran gum and 8.6 g of roast bean gum were added to 945 g of water, and the mixture was heated and stirred at 80 ° C. at 4000 rpm for 5 minutes to prepare a binder solution. While the above emulsion was stirred at 8000 rpm, the above adhesive solution was added thereto, and the stirring was continued for 5 minutes. Then, it was treated with a spray dryer (inlet temperature: 130 ° C.) to obtain vitamin E-encapsulated calcium fine particles (1680 g). Pour these particles into 85 ° C constant temperature water,
After leaving for 10 minutes, no oil (vitamin E) leakage or rancid odor was observed.

Production Example 5 (Encapsulation of Heme Iron) Rapeseed hydrogenated oil that had been heated to 80 ° C. and dissolved in advance 8
To 9 g, add 10 g of purified heme iron powder and 1 g of lecithin.
A heme iron powder dispersion is prepared by mixing. On the other hand, add milk and calcium (the same as those used in Production Example 1) to 400 g of warm water (60 ° C) and rotate at 7,000 rpm.
After pre-emulsifying for 10 minutes, the above heme iron powder dispersion was added, and the mixture was stirred at 7000 rpm for another 10 minutes and cooled. When the liquid temperature reaches 20 ° C or below, the hardened oil solidifies as fine particles of heme iron powder, and a calcium powder shell with milk protein as a sticking agent is formed around it, so centrifuge and blow dry at 40 ° C. 167g of the desired fine particles
Was obtained. A disintegration test was conducted on these microparticles using the artificial gastric juice and intestinal fluid of the Japanese Pharmacopoeia under the conditions described in Production Example 2, and it was not dissolved in gastric fluid, but dissolved in intestinal fluid containing lipase to release heme iron. There was found.

Production Example 6 (Encapsulation of erythromycin) 200 g of finely powdered erythromycin was stirred and fluidized by a fluidized bed granulator (manufactured by Freund), and 1% lecithin was added thereto.
(Merck) and 0.3% sodium alginate (manufactured by Kimitsu Chemical Co., Ltd.) in water are sprayed and dried while spraying 100 ml. This coated erythromycin powder is dispersed in 140 g of oil [“Panasate” (mark), manufactured by NOF CORPORATION). On the other hand, 400 g of 200-mesh calcium lactate (manufactured by Nippon Rika Co., Ltd.) was added to 2 liters of water and stirred at 6000 rpm for 10 minutes at high speed to prepare a dispersion liquid, and the above erythromycin dispersion liquid was added to this dispersion liquid. And continue stirring at 8000 rpm for another 10 minutes. At the end of 5 minutes during this stirring, 0.5%
Add 500 ml of sodium alginate solution. The obtained gel-containing liquid was subjected to centrifugation (3000 rpm, 10 minutes), and the precipitate was collected and dried under reduced pressure at 70 ° C. to obtain 237 g of the desired erythromycin-containing fine powder. When this fine powder was licked, no bitterness peculiar to erythromycin was observed.

[0024]

EFFECTS OF THE INVENTION A physiologically active substance which is physicochemically unstable or has an offensive odor or bitterness is completely encapsulated in a shell mainly composed of calcium, and therefore stabilizes the physiologically active substance and is also taken. It also eliminates discomfort during intake and is useful as a calcium supplement. Since it is fine particles, it is easy to take and ingest, and since the calcium shell has low thermal conductivity, it protects the encapsulated substance from external heat, and thus the fine particles according to the present invention are also used as a material for food processing. It is possible to make the encapsulated physiologically active substance enteric by making the calcium shell acid resistant.

[Brief description of drawings]

FIG. 1 is a graph showing the results of subjecting DHA-encapsulated fine particles according to the present invention and DHA-inclusion powders commercially available from various companies to an oven stability test.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-6-15162 (JP, A) JP-A-22-22221 (JP, A) JP-A-7-145044 (JP, A) JP-A-7- 124462 (JP, A) JP 62-237935 (JP, A) JP 4-27352 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/202 A23L 1 / 302 A61K 9/50 B01J 13/04

Claims (10)

(57) [Claims] 1. A bioactive substance having an oily property or an oil film
Around the periphery, fine particles for forming shells containing calcium as the main component
And the fine particles are fixed with an edible adhesive to form a shell.
Particles, and wherein said physiologically active substance in the shell is sealed. 2. The fine particles according to claim 1, wherein the edible sticking agent is at least one substance selected from milk protein and alginic acid. 3. The fine particles according to claim 1, wherein the shell is fixed together with the edible adhesive with another edible and acid-resistant second adhesive. 4. The second fixing agent is gelatin, carrageenan,
The microparticle according to claim 3, which is a combination of at least two kinds of substances selected from glucomannan, julan gum and locust bean gum. 5. Having an oily or oil film as a core-forming substance
The core form is obtained by adding a physiologically active substance to be treated, calcium fine particles as a shell-forming substance and a fixing agent to water, and stirring the water containing the additive at high speed.
Physiological activity characterized by generating zeta potential on the surface of a synthetic substance, attaching calcium fine particles and a sticking agent around the core forming substance to form a shell, and then dehydrating and drying the fine particles with the shell formed Manufacturing method of substance-encapsulated fine particles. 6. When the physiologically active substance is a hydrophilic substance,
The fine powder is coated with sodium alginate and a surfactant, and then added to oil and stirred and dispersed to prepare an emulsion containing a core-forming substance, and calcium fine particles and a suspending agent are added to water and stirred. To prepare a suspension containing the shell-forming substance, and the suspension containing the shell-forming substance is combined with the emulsion containing the core-forming substance and stirred at a high speed to form the surface of the core-forming substance.
A zeta potential is generated on the surface, and a zeta potential is generated around the core forming substance.
By attaching the fine particles of lucium to form a shell, and then adding the solution of the fixing agent and further stirring
A method for producing microparticles encapsulating a physiologically active substance , which comprises immobilizing the shell, and dehydrating and drying the microparticles in which the shell is formed . 7. When the physiologically active substance is an oily substance, it is added to water and stirred to emulsify to prepare a core-forming substance-containing emulsion, and calcium fine particles and a suspending agent are added to water and stirred. To prepare a shell-forming substance-containing suspension by dispersing calcium fine particles, and the shell-forming substance-containing suspension and the above-mentioned core-forming substance-containing emulsion are combined and stirred at a high speed to remove the core-forming substance. table
A zeta potential is generated on the surface, and a zeta potential is generated around the core forming substance.
By attaching the fine particles of lucium to form a shell, and then adding the solution of the fixing agent and further stirring
A method for producing microparticles encapsulating a physiologically active substance , which comprises immobilizing the shell, and dehydrating and drying the microparticles in which the shell is formed . 8. High speed stirring is 3000-10000 rpm
The method according to claim 5, 6 or 7, characterized in that 9. The method according to claim 5, 6 or 7, wherein at least one substance selected from calcium fine particles and milk protein as a shell-forming substance and an edible fixing agent are used. 10. A physiologically active substance-enclosed solid shell is added to a solution obtained by heating and dissolving at least two kinds of substances selected from gelatin, carrageenan, glucomannan, duran gum, sodium alginate and locust bean gum, and then stirring. 5-9 characterized by performing.
The method according to any one of 1.