CN102430377A - Method for preparing hollow microcapsules with micron sized walls by inducing templates - Google Patents

Abstract

The invention discloses a method for preparing hollow microcapsules with micron sized walls by inducing templates, comprising the following steps: dispersing the calcium carbonate colloid micro-particles in weakly acidic chitosan liquid; partially dissolving the calcium carbonate so that the pH value of a system is increased, the chitosan is deposited from the liquid and deposited on the surfaces of the colloid micro-particles; washing after absorbing; finally removing the calcium carbonate colloid micro-particles through ethylene diamine tetraacetic acid disodium salt, and obtaining the hollow microcapsules of which the thickness of the walls is micron sized. The invention has simple technology process, fast preparation speed, good controllability, wide material source and low price, so the method can be used for quickly preparing the hollow microcapsules in batches. Because the walls of the hollow microcapsules are thick and the hollow microcapsules have multiple active groups, the hollow microcapsules can be used for easily loading drugs and can be easily modified.

Description

A kind of method of utilizing template mediation to prepare hollow microcapsule with micron order cyst wall

Technical field

The present invention relates to a kind of method for preparing micron order cyst wall hollow microcapsule.Especially utilize template being partly dissolved and causing system pH to raise in weakly acidic solution, and then cause that polyelectrolyte deposits at template surface, form the method for hollow microcapsule after the stoning.

Background technology

Microcapsules are through film forming matter the space in the capsule and the capsule external space to be kept apart to form the material of particular geometric configuration.The shape of microcapsules is main with spherical structure, also can be oval, square or rectangular, polygonal and various irregularly shaped.

The preparation method of microcapsules has a lot.According to the principle of cyst wall formation, the traditional preparation process of microcapsules technology cardinal principle can be divided three classes: the physical method of the chemical method of utilization reaction generation cyst wall, the physico-chemical process that utilizes the formation cyst wall that is separated and utilization machinery or other physical action formation cyst wall.Cyst wall is made up of natural or synthetic macromolecular material usually, also inorganic compound.But the microcapsules of method for preparing or size are even inadequately, and wall thickness is wayward, perhaps relate to shortcomings such as organic solvent, have limited it and have promoted the use of.

The cavity of hollow microcapsule and cyst wall two parts all can be used for medicine and load.The permeability of the cyst wall of microcapsules and the release performance of embedding substance can be controlled through environmental condition such as temperature, ionic species and ionic strength, pH value, SOLUTION PROPERTIES, light, electricity, sound etc.; Also can be through the regulation and control wall thickness medicine carrying amount and the rate of drug release of regulating microcapsules easily, thus be more widely used in fields such as the embedding of useful for drug delivery, enzyme and catalytic reaction, organizational projects.Than additive method, the size of the hollow microcapsule that template prepares is more easy to control, also more even.Mould plate technique usually need combine other method such as polymerization, emulsification, assembling etc. could obtain microcapsules; The removal condition of often comparatively loaded down with trivial details, the consuming time length of these processes, template is comparatively harsh, cyst wall is thin is difficult for functionalization, thereby a large amount of fast preparation remains a challenge.These drawbacks limit its promotion and application, especially be difficult to adapt to the extensive requirement of preparation fast.

Summary of the invention

The purpose of this invention is to provide a kind of method of utilizing template mediation to prepare hollow microcapsule simply and rapidly with micron order cyst wall.

The method of utilizing template mediation to prepare the hollow microcapsule with micron order cyst wall of the present invention may further comprise the steps:

1) with Na ₂CO ₃Be made into concentration and be 0.33 mole the aqueous solution, Ca (NO ₃) ₂Be made into concentration and be 0.33 mole the aqueous solution, with Na ₂CO ₃The aqueous solution joins Ca (NO rapidly ₃) ₂In the aqueous solution, Na ₂CO ₃The aqueous solution and Ca (NO ₃) ₂The volume ratio of the aqueous solution is 1:1, continues to stir 30-120 second, and standing and reacting is collected the gained particulate then, uses water washing, obtains CaCO ₃Particulate;

2) with 5ml, the pH value is 5.2, and concentration is the shitosan sodium chloride solution of 2mg/ml or the CaCO of chitosan solution and 50mg step 1) gained ₃Particulate mixes, and concussion obtains the CaCO that surface deposition has shitosan ₃Colloidal particles, washing; The CaCO that perhaps surface deposition that obtains is had shitosan ₃Colloidal particles repeat and 5ml, and the pH value is 5.2, and concentration is that shitosan sodium chloride solution or the chitosan solution of 2mg/ml mixes, and washing is kept in the water;

3) with pH=7, concentration is 0.2 mole disodium ethylene diamine tetra-acetic acid solution and step 2) surface deposition of gained has the CaCO of shitosan ₃Colloidal particles solution mixes, and removes CaCO ₃Particulate obtains hollow microcapsule.

Among the present invention, said chitosan microcapsules is used CS _nExpression, n representes to deposit different number of times.

Principle of the present invention is: at calcium carbonate microparticle with after shitosan sodium chloride solution or chitosan solution mix; Because calcium carbonate particle is slowly dissolving under solutions of weak acidity; Thereby chitosan solution pH is raise; The chitosan molecule deprotonation, thus be precipitated out, and deposit to the uniform film of colloidal particles surface formation.Remove obtain after the template in water can stable existence the hollow microcapsule with micron order cyst wall.Through regulating step 2) CaCO ₃The number of times that mixes of colloidal particles and chitosan solution can be controlled the wall thickness of gained hollow microcapsule.

Beneficial effect of the present invention is:

Technical process of the present invention is simple, and preparation speed is fast, and controllability is good, and the extensive and low price of material source is suitable for a large amount of fast preparations of hollow microcapsule; The hollow microcapsule that obtains is because the thicker and multi-active base group of cyst wall has characteristics such as the drug loading of being easy to, easy modification.

Description of drawings

Fig. 1 is CaCO a) ₃The stereoscan photograph of particulate, b) CaCO ₃Stereoscan photograph after amplify the part of particulate;

Fig. 2 is CS ₁The dried stereoscan photograph of hollow microcapsule;

Fig. 3 is CS ₁The Laser Scanning Confocal Microscope photo of hollow microcapsule.Microcapsules are dispersed in the water, and shitosan is by rhodamine isothiocyanates mark;

Fig. 4 is CS ₁The transmission electron microscope photo of hollow microcapsule freezing microtome section;

Fig. 5 is CS ₂The laser confocal microscope photo of hollow microcapsule;

Fig. 6 is CS ₃The laser confocal microscope photo of hollow microcapsule;

Fig. 7 is CS ₄The laser confocal microscope photo of hollow microcapsule;

Fig. 8 is CS ₅The laser confocal microscope photo of hollow microcapsule;

Fig. 9 is CS ₆The laser confocal microscope photo of hollow microcapsule;

Figure 10 is CS ₆The dried stereoscan photograph of hollow microcapsule;

Figure 11 is CS ₆The transmission electron microscope photo of hollow microcapsule freezing microtome section.

The specific embodiment

Further specify the present invention below in conjunction with instance, but these instances are not used for limiting the present invention.

For wall thickness and the CaCO that clearlys show hollow microcapsule ₃Colloidal particles are relevant with chitosan solution mixing number of times; Adopt shitosan (TRITC-CS) solution of rhodamine isothiocyanates mark or shitosan (FITC-CS) sodium chloride solution of marked by fluorescein isothiocyanate in the following instance, so that directly observe through Laser Scanning Confocal Microscope.The content of these fluorescent dyes is very low, does not influence the physical and chemical performance of shitosan.

Embodiment 1

1) with Na ₂CO ₃And Ca (NO ₃) ₂Be made into the aqueous solution of 0.33 mole and 0.33 mole respectively, under the 700r/min mechanical agitation, with Na ₂CO ₃The aqueous solution joins Ca (NO rapidly ₃) ₂In the aqueous solution, Na ₂CO ₃The aqueous solution and Ca (NO ₃) ₂The volume ratio of the aqueous solution is 1:1, continues to stir 30 seconds, and standing and reacting is collected the gained particulate then, uses water washing, obtains CaCO ₃Particulate, about 6～8 microns of particle diameter is seen Fig. 1;

2) with 5ml, pH=5.2, concentration is the TRITC-CS sodium chloride solution of 2mg/ml and the CaCO of 50mg step 1) gained ₃Particulate mixes, and concussion 10min obtains the CaCO that surface deposition has TRITC-CS ₃Colloidal particles are washed three times, are kept in the water;

3) with pH=7, concentration is 0.2 mole disodium ethylene diamine tetra-acetic acid solution and step 2) surface deposition of gained has the CaCO of shitosan ₃The colloidal particles aqueous solution is removed CaCO ₃Particulate obtains hollow microcapsule.

This routine CaCO ₃Colloidal particles and shitosan sodium chloride solution mix 1 time, and the hollow microcapsule that makes is designated as CS ₁See Fig. 2 after the drying, the Laser Scanning Confocal Microscope photo is seen Fig. 3, and transmission electron microscope section photo is seen Fig. 4;

Embodiment 2

Step 1) is with instance 1 step 1);

Step 2) with the step 2 of instance 1), difference is that used shitosan sodium chloride solution is unlabelled shitosan;

Step 3) is with the step 3) of instance 1.

Embodiment 3

Step 1) is with instance 1 step 1), and difference is that mixing time is 1 minute, the CaCO for preparing ₃The diameter of particulate is about 4 microns;

Step 2), 3) with the step 2 of instance 1), 3).

Embodiment 4

Step 1) is with instance 1 step 1), and difference is that stir speed (S.S.) is 600r/min, and the time is 1 minute, the CaCO for preparing ₃The diameter of particulate is about 10～12 microns;

Step 2) with the step 2 of instance 1), difference is TRITC-CS solution and CaCO ₃Particulate mixes; Step 3) is with the step 3) of instance 1.

Embodiment 5

Step 1) is with instance 1 step 1);

Step 2): with 5ml, the pH value is 5.2, and concentration is the TRITC-CS sodium chloride solution of 2mg/ml and the CaCO of 50mg step 1) gained ₃Particulate mixes, and concussion obtains the CaCO that surface deposition has TRITC-CS ₃Colloidal particles, washing; The CaCO that the surface deposition that obtains is had the shitosan of TRITC-CS ₃Colloidal particles and 5ml, the pH value is 5.2, and concentration is that the FITC-CS sodium chloride solution of 2mg/ml mixes, and washing is kept in the water;

Step 3) is with the step 3) of instance 1.

This routine CaCO ₃Colloidal particles and shitosan sodium chloride solution mix 2 times, and the hollow microcapsule that obtains is designated as CS ₂, Laser Scanning Confocal Microscope photo such as Fig. 5.

Embodiment 6

Step 1) is with instance 1 step 1);

Step 2): with 5ml, the pH value is 5.2, and concentration is the TRITC-CS sodium chloride solution of 2mg/ml and the CaCO of 50mg step 1) gained ₃Particulate mixes, and concussion obtains the CaCO that surface deposition has TRITC-CS ₃Colloidal particles, washing; The CaCO that the surface deposition that obtains is had TRITC-CS ₃Colloidal particles and 5ml, the pH value is 5.2, concentration is that the FITC-CS sodium chloride solution of 2mg/ml mixes washing; With 5ml, the pH value is 5.2, and concentration is the TRITC-CS sodium chloride solution and the CaCO that deposits FITC-CS of 2mg/ml ₃Particulate mixes, concussion, and washing is kept in the water;

Step 3) is with the step 3) of instance 1.

This routine CaCO ₃Colloidal particles and shitosan sodium chloride solution mix 3 times, and the hollow microcapsule that obtains is designated as CS ₃, Laser Scanning Confocal Microscope photo such as Fig. 6.

Embodiment 7

Step 1) is with instance 1;

Step 2), 3) with the step 2 of instance 4), 3).

This routine CaCO ₃Colloidal particles and shitosan sodium chloride solution mix 4 times, and the hollow microcapsule that obtains is designated as CS ₄, Laser Scanning Confocal Microscope photo such as Fig. 7.

Embodiment 8

Step 1) is with instance 1;

Step 2), 3) with the step 2 of instance 4), 3).

This routine CaCO ₃Colloidal particles and shitosan sodium chloride solution mix 5 times, and the hollow microcapsule that obtains is designated as CS ₅, Laser Scanning Confocal Microscope photo such as Fig. 8.

Embodiment 9

Step 1) is with instance 1;

Step 2), 3) with the step 2 of instance 4), 3).

This routine CaCO ₃Colloidal particles and shitosan sodium chloride solution mix 6 times, and the hollow microcapsule that obtains is designated as CS ₆, Laser Scanning Confocal Microscope photo such as Fig. 9, stereoscan photograph such as Figure 10, transmission electron microscope section photo such as Figure 11.

Visible by accompanying drawing 5-9, along with CaCO ₃Colloidal particles and shitosan sodium chloride solution mixing number of times increase, and the hollow microcapsule wall thickness increases.

Claims (1)

1. one kind is utilized the template mediation preparation to have the method for the hollow microcapsule of micron order cyst wall, may further comprise the steps:

1) with Na ₂CO ₃Be made into concentration and be 0.33 mole the aqueous solution, Ca (NO ₃) ₂Be made into concentration and be 0.33 mole the aqueous solution, with Na ₂CO ₃The aqueous solution joins Ca (NO rapidly ₃) ₂In the aqueous solution, Na ₂CO ₃The aqueous solution and Ca (NO ₃) ₂The volume ratio of the aqueous solution is 1:1, continues to stir 30 ~ 120 seconds, and standing and reacting is collected the gained particulate then, uses water washing, obtains CaCO ₃Particulate;

2) with 5ml, the pH value is 5.2, and concentration is the shitosan sodium chloride solution of 2mg/ml or the CaCO of chitosan solution and 50mg step 1) gained ₃Particulate mixes, and concussion obtains the CaCO that surface deposition has shitosan ₃Colloidal particles, washing; The CaCO that perhaps surface deposition that obtains is had shitosan ₃Colloidal particles repeat and 5ml, and the pH value is 5.2, and concentration is that shitosan sodium chloride solution or the chitosan solution of 2mg/ml mixes, and washing is kept in the water;

3) with pH=7, concentration is 0.2 mole disodium ethylene diamine tetra-acetic acid solution and step 2) surface deposition of gained has the CaCO of shitosan ₃The colloidal particles aqueous solution is removed CaCO ₃Particulate obtains hollow microcapsule.

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