KR100919508B1 - Alginate particle containing calcium carbonate in matrix and the method for production of the said alginate particle - Google Patents

Abstract

The present invention is characterized by releasing calcium carbonate in a matrix of alginate particles trapping a target substance, thereby releasing a relatively small amount of the target substance at basic pH, and releasing a relatively large amount of the target substance at acidic pH. have.

Description

Alginate particle containing calcium carbonate in matrix and the method for production of the said alginate particle}

The present invention relates to alginate particles containing calcium carbonate. More specifically, the present invention relates to alginate particles which contain calcium carbonate in the matrix, thereby releasing relatively less target substance at basic pH and relatively more target substance at acidic pH.

Alginates are obtained in the form of salts of alginic acid, mainly from brown algae (Pillay V and Fassihi R. 1999. Journal of Controlled Release 55: 45-55, Kim SR et al., 1997. European Polymer Journal 33: 1009 -1014).

Alginate is Ca ^{2 +,} Mg ^{2 +} there is gelled in aqueous solution with dissolved multivalent cations (divalent or more cation), such as (Ouwerx C. Et al, 1998. Polym Gels Netw 6:.... 393-408), alginate This is because a high mechanical strength gel is formed by the electrostatic attraction between the carboxylate group and the polyvalent cation of (Melzoch K et al., 1994. Journal of Biotechnology 32: 59-65). The microspheres or macrospheres are prepared using these characteristics, and the microparticles are prepared using a spray method or the like, and the macroparticles are used to drop an alginate solution into a polyvalent cation solution. It is manufactured by.

The alginate particles that collect the target substance are prepared by dissolving the target substance in an alginate solution and then dispersing it in a solution containing a cation. The target substance contained in the alginate particles is obtained by simple diffusion due to the difference in concentration between the inside and the outside of the particle. Emitted to the outside. That is, slow release.

However, such a formulation does not release the target substance collected therein to the outside only under specific conditions, but releases the target substance collected therein under all general conditions to the outside. For example, at the low temperature, the room temperature, and the high temperature, the target substance captured by simple diffusion is released to the outside without any significant difference, and the target substance collected by simple diffusion is released to the outside without a distinct difference at acidic, neutral, and basic pH. It is.

Therefore, there has been a need for the development of alginate particles in which the formulation is designed to release the target substance to the outside only under certain conditions.

On the other hand, as an example of a patent technology related to the alginate particles collected in the prior art, Korean Patent Publication No. 10-2006-0133122 (published date: December 26, 2006) '(a) preparing wasabi horseradish extract; (b) concentrating wasabi extract of step (a); (c) mixing the wasabi extract and the alginate solution of step (b); (d) spraying the mixed solution of step (c) into the polyvalent cation solution through a nozzle; And (e) preparing a method for preparing alginate microcapsules containing horseradish extract including washing and drying the microcapsules formed in step (d).

However, the alginate microcapsules disclosed in this patent invention only serve to mask the strong irritantness and high volatility of the collected wasabi extract, and selectively select the components trapped inside, that is, horseradish extract under specific conditions. There was no mention of the technical idea of releasing.

Accordingly, the present invention has been made in view of developing and providing alginate particles which can release a target substance only under specific conditions.

In order to achieve the above object, the present invention provides an alginate particle, characterized in that calcium carbonate is contained in the alginate matrix in the alginate particles that collect the target substance.

In addition, the present invention comprises the steps of preparing a calcium carbonate-alginate mixture by mixing a solution or suspension containing calcium carbonate in a solution or suspension containing the alginate and the target substance to be collected; And dripping or spraying the calcium carbonate-alginate mixture into a polyvalent cation solution.

In addition, the present invention comprises the steps of preparing a calcium carbonate-alginate mixture by mixing a solution or suspension containing calcium carbonate in a solution or suspension containing the alginate and the target substance to be collected; Spray-drying the calcium carbonate-alginate mixture to prepare calcium carbonate-alginate composite particles; And adding the calcium carbonate-alginate composite particles to the polyvalent cation-containing solution.

In the present invention, calcium carbonate microparticles are embedded in the alginate particles so as to release the target substance collected only at an acidic pH (hereinafter, referred to as 'calcium carbonate-alginate composite particles').

As shown in Figure 1, calcium carbonate is very well soluble in acidic solutions and hardly soluble in neutral and basic solutions, so calcium carbonate microparticles can be leached out of the matrix of alginate particles in acidic solutions. As a result, a cavity is formed in the alginate matrix, through which the target material can be released quickly.

On the other hand, calcium carbonate hardly dissolves in neutral and basic solutions, and therefore calcium carbonate particles hardly dissolve from the matrix of alginate particles in neutral and basic solutions. As a result, no pupil is formed in the matrix of the alginate particles, and the target substance is gradually released only by simple diffusion. That is, the calcium carbonate-alginate composite particle of the present invention is a formulation that releases a large amount of a target substance only in an acidic state, and releases a small amount of a target substance in a neutral and basic state.

Hereinafter, a method of preparing alginate particles in which calcium carbonate of the present invention is contained in an alginate matrix will be described in more detail.

In the present invention, "% concentration" means "mass / mass%" unless otherwise specified.

The present invention provides two methods for producing alginate particles in which calcium carbonate is contained in the alginate matrix.

The first method includes preparing a calcium carbonate-alginate mixture by mixing a solution or suspension containing calcium carbonate with a solution or suspension containing alginate and a target substance to be collected; And dropping or spraying the calcium carbonate-alginate mixture into a polyvalent cation solution.

The second method includes preparing a calcium carbonate-alginate mixture by mixing a solution or suspension containing calcium carbonate with a solution or suspension containing alginate and a target substance to be collected; Spray-drying the calcium carbonate-alginate mixture to prepare calcium carbonate-alginate composite particles; And adding the calcium carbonate-alginate composite particles to the polyvalent cation-containing solution.

On the other hand, in the first or second alginate particle production method of the present invention, the solution or suspension containing the alginate and the target material to be collected; And a solution or suspension containing calcium carbonate; preferably, the mixing ratio is such that the content ratio of alginate and calcium carbonate in the calcium carbonate-alginate mixture is 100: 1 to 1:10 based on the solid content. When the calcium carbonate content is low, it does not have the characteristic of releasing a large amount of the target component only in acidity, and when the content is large, the alginate content in the composite particles is small, so that the mechanical strength of the particles is low and the amount of the target component that can be encapsulated is small. Because it is generated. At this time, the content ratio of the alginate and calcium carbonate is more preferably 50: 1 to 1: 5, most preferably 10: 1 to 1: 1.

On the other hand, in the first or second alginate particle production method of the present invention, the polyvalent cation solution is preferably a concentration of the polyvalent cation is 10 ~ 200 mM. Calcium carbonate-alginate composite particles do not form well at concentrations lower than this range, and calcium carbonate-alginate composite particles are poorly formed. At higher concentrations, the alginate matrix is densely contained because the crosslink density is too high. This is because calcium carbonate does not melt well even in acid. At this time, the concentration of the polyvalent cation is more preferably 30 ~ 150 mM, most preferably 50 ~ 100 mM. The multivalent cation is to refer to a divalent or more cation, Ca ^{+ 2,} Mg ^{+ 2,} Al ^{+ 3} and Cr may be at least any one selected from ^{3 +.}

Meanwhile, when preparing a macro composite particles by dropping the calcium carbonate-alginate mixture into a polyvalent cation solution, it is preferable to pass a syringe or a tube or the like.

In addition, it is preferable to use a mechanism equipped with a nozzle when preparing a micro composite particles by spraying a calcium carbonate-alginate mixture solution into a polyvalent cation solution.

On the other hand, in the second alginate particle production method of the present invention, spray drying is preferably carried out at a temperature of 100 ~ 150 ℃. This is because at lower temperatures, moisture cannot evaporate completely and dry particles cannot be obtained. At higher temperatures, alginate may be denatured. At this time, the spray drying temperature is more preferably 110 ~ 140 ℃, most preferably 115 ~ 130 ℃.

On the other hand, in the first or second alginate particle manufacturing method of the present invention, the solution or suspension containing the alginate and the target substance to be collected, preferably the concentration of alginate is 0.1 to 20%. If a concentration lower than this range is used, the strength of the produced particles is weak and easily broken. If a concentration higher than this range is used, the viscosity of the solution is too high to produce alginate particles. At this time, the concentration of the alginate is more preferably 0.5 to 10%, most preferably 1 to 5%.

Meanwhile, various hydrophobic and hydrophilic bioactive components such as anticancer agents, antibiotics, antifungal agents, antibacterial agents, antioxidants, whitening agents and anti-inflammatory agents may be used as the target ingredients.

On the other hand, in the manufacturing method of the first or second alginate particles of the present invention, the calcium carbonate particles to be used is preferably microparticles calcium carbonate. Since the microparticles of calcium carbonate are embedded in the matrix of alginate in a small size, they do not destabilize the structure of the alginate particles, and when calcium carbonate is dissolved in an acidic solution and voids are generated, a large amount of the target substance collected inside is suddenly outside. This is because the shock to the external material system can be reduced by preventing the emission.

The present invention provides a 'homogenization method' as a first method, a 'dissolution in an acidic solution and an alkali solution addition method' as a first method, and a 'spray drying method' as a third method for the fine granulation of calcium carbonate particles. . Hereinafter, each method will be described in detail.

(One) Homogenization ( homogenization ) Way

Calcium carbonate particles are microparticleed by homogenizing in solution or suspension. Preferably, the calcium carbonate is dispersed in a solution to which a dispersant is added and finely granulated by homogenizing with a homogenizer. In this case, the homogenizer may be preferably any one selected from an ultrasonic grinder, an ultrafast rotating homogenizer, and a microfluidizer.

On the other hand, the calcium carbonate is preferably in a concentration of 0.1 to 50% in the solution to which the dispersant is added. This is because at lower concentrations, the calcium carbonate content in the calcium carbonate-alginate composite particles is so low that the desired release characteristics cannot be obtained. At higher concentrations, the slurry is in a slurry state and cannot be effectively homogenized. At this time, the concentration of the calcium carbonate is more preferably 0.2 to 20%, most preferably 0.3 to 10%.

On the other hand, the dispersant is preferably a concentration of 0.001 ~ 20% in the solution to which the dispersant is added. If it is out of this range, the fine particles can not aggregate to obtain a uniform solution or suspension. At this time, the concentration of the dispersant is more preferably 0.01 to 5%, most preferably 0.1 to 1%.

On the other hand, the dispersant is preferably HLB number (Hydrophilic Lipophilic Balance number) is 5-11. If the HLB number is out of this range, the fine particles can aggregate to obtain a uniform suspension. At this time, the HLB number is more preferably 6-10, most preferably 7-9. Amphipathic molecules with these characteristics include tween 20, sorbitan monolaurate, sorbitan monopalmitate, soya lecithin, and polyvinyl alcohol. vinyl alcohol)).

(2) dissolved in acidic solution and Alkali  Method of addition of solution

Calcium carbonate is dissolved in an acidic solution, and an alkali solution is added to prepare microparticulated calcium carbonate. At this time, the concentration of calcium carbonate in the acidic solution is preferably 0.1 to 6%. This is because calcium particles are not formed even if the alkali solution is added at a lower concentration. At higher concentrations, the calcium fine particles are not less than the solubility. At this time, the concentration of the calcium carbonate is more preferably 0.2 to 5.5%, most preferably 0.3 to 5%.

On the other hand, it is preferable that the dispersant is added to the acidic solution, and the dispersant is preferably in a concentration of 0.001 to 20% in the solution to which the dispersant is added. It is preferable that the said dispersing agent is 5-11 of HLB numbers, More preferably, it is 6-10, Most preferably, it is 7-9. The role and action of the dispersant are as described in the '(1) homogenization method'.

(3) spray drying method

Calcium carbonate is dissolved in an acidic solution and spray-dried to obtain finely divided calcium carbonate. At this time, the concentration of calcium carbonate in the acidic solution is preferably 0.1 to 10%.

On the other hand, the acidic solution is preferably a dispersing agent is added, the dispersing agent is preferably a concentration of 0.001 to 20% in the solution to which the dispersing agent is added, the dispersing agent is preferably HLB number 5-11, more preferably 6-10 Most preferably, it is 7-9. The role and action of the dispersant are as described in the '(1) homogenization method'.

As described above, the present invention is characterized in that the alginate particles containing calcium carbonate in the matrix can release relatively little target substance collected at basic pH and release relatively much target substance collected at acidic pH. As such, various hydrophobic and hydrophilic bioactive components such as anticancer agents, antibiotics, antifungal agents, antibacterial agents, antioxidants, whitening agents, and anti-inflammatory agents collected therein can be selectively released to the outside depending on the situation.

1 is the solubility of calcium carbonate with pH

Figure 2 is the result of measuring the size of the calcium carbonate microparticles by light scattering method.

3 is an electron micrograph of calcium carbonate particles prepared by spray drying.

Figure 4 is an electron micrograph of the cross section of the calcium carbonate-alginate composite particles.

5 is a result of measuring the release rate according to the pH of the alginate particles and calcium carbonate-alginate composite particles for 12 hours. ●: alginate particles, ○: calcium carbonate-alginate composite particles

Figure 6 is a result of observing the cross-section after immersing calcium carbonate-alginate composite particles in an acidic solution for 12 hours

Hereinafter, the content of the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited only to the following examples, but includes modifications of equivalent technical ideas.

Examples 1-4: Calcium Using Ultrasonic Grinding Carbonate  Microparticle Manufacturing

Calcium carbonate powder was added to 0.5% in the dispersant solution (dispersant concentration, 0.01%), and then ground by an ultrasonic grinder for 3 minutes, 10 minutes, 30 minutes. Calcium carbonate microparticles were prepared using the dispersants shown in Table 1. Figure 2 is a result of measuring the size of the calcium carbonate microparticles prepared in Example 1 by light scattering method (light scattering). As shown in FIG. 2, the ultrasonic pulverization significantly reduced the particle size. The particle size after the ultrasonic grinding was 1.8 ~ 2.2 ㎛.

division Example 1 Example 2 Example 3 Example 4 Calcium Carbonate 0.5 0.5 0.5 0.5 Poly (vinyl acohol) 0.01 - - - Tween 20 - 0.01 - - Sorbitan monopalmitate - -     0.01 - Sorbitan monopalmitate - - - 0.01 Distilled water Remainder Remainder Remainder Remainder

  (weight %)

Example 5: Calcium Using Spray Drying Method Carbonate  Preparation of Fine Particles

Dissolve 1 g of calcium carbonate powder in 100 ml of acidic solution (pH 5). Spray drying with a nozzle sprayer (BUCHI, Min Spray Dryer B-290) at an inlet temperature of 120 ° C. 3 is an electron micrograph of calcium carbonate particles prepared by spray drying. It was confirmed that the microparticles were formed on the electron microscope, the size of the particles were about several tens of ㎛.

Examples 6-15: ' Alginate  Solution 'and' calcium ' Carbonate - Alginate  Preparation of 'Mixed Liquid'

An alginate solution was prepared by dissolving blue dextran (blue dextran, molecular weight 2,000,000) as a target material for dissolving alginate in distilled water (Example 6-8; used as a control). In the case of the calcium carbonate-alginate mixture, the calcium carbonate suspension prepared in Example 1 was added to the alginate solution (Examples 9-14).

division Alginate Buldextran Calcium Carbonate Suspension of Example 1 Distilled water Example 6 One 0.4 0 Remainder Example 7 2 0.4 0 Remainder Example 8 3 0.4 0 Remainder Example 9 One 0.4 25 Remainder Example 10 2 0.4 25 Remainder Example 11 3 0.4 25 Remainder Example 12 One 0.4 50 Remainder Example 13 2 0.4 50 Remainder Example 14 3 0.4 50 Remainder

 (weight %)

Example 15-18: 'Using the dropping method Alginate  Particles' and 'calcium' Carbonate - Alzine Preparation of T 'Composite Particles

10 ml of alginate solution or 10 ml of calcium carbonate-alginate mixture was injected into a syringe as described in Table 3 below, and dropwise dropwise was added dropwise to 100 ml of CaCl ₂ solution.

division Solution of Example 8 Mixed Suspension of Example 14 50 mM CaCl ₂ solution 100 mM CaCl ₂ solution Example 15 10 ml - 100 ml - Example 16 10 ml - - 100 ml Example 17 - 10 ml 100 ml - Example 18 - 10 ml - 100 ml

As a result, round alginate particles were formed in Examples 15 to 18. 4 is a result of observing the cross section of the particles produced in Example 18. FIG. As shown in Figure 4 it was confirmed that the calcium carbonate particles are embedded in the alginate.

Evaluation example :One pH Emission behavior according to

0.1 g of the alginate particles prepared in Example 16 and the calcium carbonate-alginate composite particles prepared in Example 18 were added to 50 ml of an aqueous solution adjusted to pH 3, 4, 5, 6, 7, 8, and 9, and then The amount of blue dextran released over time was measured at 630 nm using a UV-spectrophotometer (JENWAY 6505, UK) (FIG. 5).

Alginate particles not containing calcium carbonate showed almost constant percent release regardless of pH. On the other hand, the alginate composite particles containing calcium carbonate particles showed a low release percentage in the basic aqueous solution and a high release percentage in the acidic aqueous solution.

This is because the calcium carbonate particles are hardly dissolved in the basic aqueous solution and the calcium carbonate particles are very well dissolved in the acidic aqueous solution. In other words, the reason for the high acid release is that the calcium carbonate was dissolved in the acid and a cavity was generated inside the alginate particles.

6 is a result of observing the cross-section after immersing the calcium carbonate-alginate composite particles in an acidic solution for 12 hours, it was confirmed that the cavity (cavity) was formed inside the particle.

As in Evaluation Example 1, the calcium carbonate-alginate composite particles prepared by the preparation method of the present invention showed a high emission% in an acidic aqueous solution and a low emission% in an alkaline aqueous solution.

Claims (24)

delete Containing fine granulated calcium carbonate prepared by dissolving calcium carbonate with different solubility according to pH in an acid solution and adding it to an alkaline solution in a solution or suspension containing alginate and a target substance to be collected. Mixing a solution or suspension to prepare a calcium carbonate-alginate mixture; And, Dropping or spraying the calcium carbonate-alginate mixture into a solution containing Ca ²⁺ , Mg ²⁺ , Al ³⁺ and Cr ³⁺ ; Method of producing elutable alginate particles Containing fine granulated calcium carbonate prepared by dissolving calcium carbonate with different solubility according to pH in an acid solution and adding an alkaline solution to a solution or suspension containing alginate and a target substance to be collected. Mixing a solution or suspension to prepare a calcium carbonate-alginate mixture; Spray-drying the calcium carbonate-alginate mixture to prepare calcium carbonate-alginate composite particles; And, Adding the calcium carbonate-alginate composite particles to a solution containing Ca ²⁺ , Mg ²⁺ , Al ³⁺ and Cr ³⁺ ; optionally eluting the target substance to the outside according to a change in pH Process for producing alginate particles The method according to claim 2 or 3, A solution or suspension containing the alginate and the target substance to be collected; And a solution or suspension containing finely granulated calcium carbonate prepared by dissolving calcium carbonate having a different solubility according to pH in an acidic solution by 0.1 to 6% by weight and adding an alkaline solution. Optionally mix the target substance with the change of pH, characterized by mixing so that the content ratio of the alginate and calcium carbonate in the calcium carbonate-alginate mixture with different solubility according to pH is 100: 1 to 1:10 based on each solid content. Method for producing alginate particles that can be eluted with The method according to claim 2 or 3, The Ca ²⁺ , Mg ²⁺ , Al ³⁺ and Cr ³⁺ containing solution, Method for producing alginate particles that can elute the target material to the outside selectively according to the pH change, characterized in that the concentration of Ca ²⁺ , Mg ²⁺ , Al ³⁺ and Cr ³⁺ is 10 ~ 200 mM delete The method of claim 3, The spray drying, Method for producing alginate particles that can selectively elute the target material to the outside according to the pH change characterized in that carried out at a temperature of 100 ~ 150 ℃ The method according to claim 2 or 3, The solution or suspension containing the alginate and the target substance to be collected, Method for producing alginate particles which can selectively elute the target substance to the outside according to the pH change, characterized in that the concentration of alginate is 0.1 to 20% by weight. delete delete delete delete delete delete delete delete The method according to claim 2 or 3, The acidic solution, Method for producing alginate particles which can elute the target material to the outside selectively according to the pH change characterized in that the dispersing agent having a HLB number (Hydrophilic Lipophilic Balance number) is 5-11. The method of claim 17, The concentration of the dispersant having the HLB number (Hydrophilic Lipophilic Balance number) 5-11, Method for producing alginate particles that can elute the target material to the outside selectively according to the change in pH, characterized in that the HLB number (Hydrophilic Lipophilic Balance number) 5 to 11 of the dispersant added solution is 0.001 to 20% by weight delete delete delete delete delete delete