WO2019232823A1 - Preparation for chitosan and propylene glycol alginate blended microcapsule and application thereof - Google Patents

Abstract

Provided are preparation for a chitosan and propylene glycol alginate blended microcapsule and an application thereof, pertaining to the field of preparation and application of microcapsules. The preparation comprises dissolving chitosan with an acetic acid solution having a mass percentage concentration of 0.5-5%, dissolving propylene glycol alginate with water, then mixing the two solutions, introducing a 2-8% aqueous solution of NaOH in a high-voltage electrostatic field to form wet blended microcapsules, and then washing and drying the wet blended microcapsules to obtain dry blended microcapsules. The prepared chitosan and propylene glycol alginate blended microcapsule can be used as an embolic material for vascular embolization, where the embolic material is injected or fed into a target blood vessel through a catheter to occlude the blood vessel at a target position. Good expansion properties of the embolic material can avoid the migration of microcapsules in blood vessels, and the stable structure thereof can stabilize embolisms. Further, the blended microcapsule is applicable to sustained-release drugs as a carrier for a sustained-release drug, achieving the effect of desirable sustained release of the drug by combining the blended microcapsule with the drug.

Description

Preparation and application of chitosan and propylene glycol alginate blend microcapsules Technical field

The invention relates to the field of preparation and application of microcapsules, in particular to preparation and application of a chitosan and propylene glycol alginate blended microcapsule.

Background technique

Chitin (also known as chitin, chitin, chitin, and crab shell) is the second largest natural polymer material after cellulose. Its chemical structure is (1,4) -2-acetamido-2 -Deoxy-β-D-glucan. Chitosan (also known as chitosan) is a kind of polymer amino polysaccharide obtained by deacetylation of chitin. Its molecular structure is (1,4) -2-amino-2-deoxy-β-D-glucose Glycan. Chitosan can be dissolved in dilute acid solution and processed into films, fibers and microcapsules. Chitosan has good biocompatibility, biodegradability, hemostasis, and promotion of wound healing. It is used in surgical sutures, medical dressings, artificial skin, hard tissue repair materials, artificial kidney membranes, antibacterial materials, and health care. There are a wide range of applications in underwear fabrics, drug sustained-release materials, and facial masks.

Alginic acid is an acidic polysaccharide extracted from seaweed. It is a natural polymer copolymer composed of α-L-guluronic acid and β-D-mannuronic acid. Alginic acid is widely present in brown algae, and dried brown algae contains about 20-30% of alginic acid. After the seaweed is harvested, the extraction process of alginic acid includes washing with water, grinding, and then dissolving the alginic acid in the alga with an alkaline solution. After further separation and filtration, the alginic acid extracted from the seaweed is dried, ground, and neutralized to form a water-soluble sodium alginate powder.

Propylene alginate (PGA, also known as propylene glycol alginate) is a functional polymer material obtained by esterifying alginic acid with propylene oxide. As a non-ionic alginic acid derivative, propylene glycol alginate has unique colloidal properties and thickening, stability, emulsifying, suspending, film-forming, and ability to form gels. It is used in food and medicine and health The field has unique applications. Because some of the carboxylic acid groups in alginic acid are esterified with propylene glycol, PGA can be dissolved in water to form a solution. Its salt resistance is strong, and it is stable to metal ions such as calcium and sodium. Salting out does not occur even in concentrated electrolyte solutions. .

As a non-ionic water-soluble polymer, propylene glycol alginate and sodium carboxymethyl cellulose, modified starch, sodium alginate, acacia gum, pectin, peach gum, etc. have good mutual solubility, and can be mixed and mixed. use. Under acidic conditions, PGA has a unique role in stabilizing proteins. Under weak alkaline conditions, the cross-linking reaction between PGA and protein occurs due to the reaction of the ester bond and amino group in PGA. At 40-50 ° C, PGA can react with gelatin to obtain a fast-setting gel. This gel is irreversible in boiling water.

As polymer materials, both chitosan and propylene glycol alginate can be processed into microspheres and microcapsules when used alone. However, due to the lack of hydrophilic and water-retaining groups in the molecular structure of chitosan, the pure shell polymer products have poor water-swellability. And propylene glycol alginate is a non-ionic water-soluble polymer. Although it can be processed into microspheres and microcapsules, it is not easy to form a cross-linked structure during processing, so that the pure propylene glycol alginate product after water contact Dissolves, lacks structural stability during application.

Summary of the Invention

Based on the above background, one of the objectives of the present invention is to provide a preparation of chitosan and propylene glycol alginate blended microcapsules, and to prepare the microcapsules in a specific preparation environment; another object of the present invention is to provide chitosan New use of microcapsules blended with propylene glycol alginate, that is, new applications in the medical field.

The present invention adopts the following technical solutions:

A method for preparing chitosan and propylene glycol alginate blended microcapsules adopts the following steps:

The chitosan is dissolved with a 0.5% -5% acetic acid solution, the propylene glycol alginate is dissolved with water, and then the two solutions are mixed and squeezed into a 2-8% NaOH aqueous solution under a high-voltage electrostatic field to form a wet state. The blended microcapsules are washed and dried to obtain a dry blended microcapsule.

Preferably, the voltage of the high-voltage electrostatic field is 1-12kv, the pulse width is 1-6ms, and the frequency is 10-350Hz.

Preferably, the voltage of the high-voltage electrostatic field is 8 kv, the pulse width is 3 ms, and the frequency is 100 Hz.

Preferably, the mass concentration of the chitosan solution formed by dissolving the chitosan with an acetic acid solution having a mass concentration of 0.5-5% is 0.5-5%, and the mass of the propylene glycol alginate solution formed by dissolving the propylene glycol alginate in water The percentage concentration is 0.5-5%.

Preferably, the chitosan and the propylene glycol alginate can be mixed in any ratio.

Preferably, the weight ratio of the chitosan and the propylene glycol alginate is (1-10): 1.

In order to better understand the above technical solution, the reaction principle is briefly explained:

Since chitosan is a cationic polyelectrolyte and a basic polysaccharide, it can be dissolved in a dilute acid solution to obtain a uniform chitosan solution. Propylene glycol alginate is a non-ionic water-soluble polymer, which can obtain a uniform solution after dissolving in water. After the two are mixed, since propylene glycol alginate has acid resistance, the two polymers have good compatibility at the initial stage of mixing, and a uniform mixed solution can be obtained under stirring.

Chitosan and propylene glycol alginate blend microcapsules contain both chitosan and alginic acid, which are biologically active natural polymer materials. The transesterification reaction between chitosan and propylene glycol alginate is used to form a stable crosslinked structure through the reaction of the amino group in chitosan with the ester group in propylene glycol alginate during the drying process of the blended microcapsules. Blend microcapsules of chitosan with propylene glycol alginate. This reaction makes the blended material obtained after drying have good moisture stability, is insoluble in water, but can absorb a large amount of water. And by changing the mass ratio between chitosan and propylene glycol alginate, blended microcapsules with different hygroscopic swelling properties can be obtained.

In addition, the present invention relates to the use of chitosan and propylene glycol alginate blended microcapsules as embolic substances.

A method of using chitosan and propylene glycol alginate blended microcapsules as an embolic substance: using the wet blended microcapsules as an embolic substance, injecting or feeding the embolic substance into a target blood vessel through a catheter; and occluding the blood vessel at the target site. So as to achieve the intended therapeutic purpose.

The invention relates to the application of chitosan and propylene glycol alginate blended microcapsules to a sustained-release medicine.

Application method of chitosan and propylene glycol alginate blended microcapsules for sustained-release drugs: Chitosan and propylene glycol alginate blended microcapsules are used as slow-release drug carriers, and chitosan and propylene glycol alginate are used Blending microcapsules and drugs to achieve the effect of sustained release of drugs.

The technical effect directly brought by the above technical solution is that the wet blended microcapsules have good biocompatibility, biodegradability, natural non-toxicity and bacteriostasis, and have good application prospects in the field of medicine. The wet-mixed microcapsules are used as embolic substances, and the embolic substances are injected or delivered into the target blood vessel through a catheter to occlude the blood vessels to achieve the intended therapeutic purpose. It achieves the purpose of treatment by blocking blood flow in the blood vessels and reducing blood supply to the lesion or a specific part of the body. This kind of wet blended microcapsule has better embolization effect and higher targeting to specific tissues and organs.

Microcapsules can be combined with drugs to achieve the effect of sustained release of drugs. Using the wet-blended microcapsules as a slow-release drug carrier, the drug is slowly released in the body with a stable concentration, which improves the safety of the drug, while traditional drugs are released in large quantities within a short period of time, which causes the drug level in the serum to rapidly increase and the drug to reach its peak. The concentration decreases rapidly. The wet-blended microcapsules are harmless to the human body, have good biocompatibility, can be degraded, or can be completely excreted from the body. They have higher biological safety and are ideal for slow-release drug carriers.

The present invention relates to the application of chitosan and propylene glycol alginate blended microcapsules in planting and intervening materials.

The invention relates to the application of chitosan and propylene glycol alginate blended microcapsules in cosmetics.

The invention relates to the application of chitosan and propylene glycol alginate blended microcapsules in functional foods.

The invention relates to the application of chitosan and propylene glycol alginate blended microcapsules in the controlled release of fertilizers.

The beneficial effects of the present invention are:

The prepared chitosan and propylene glycol alginate blended microcapsules have good structural stability while having high hygroscopic swelling properties; they can achieve good sustained-release properties when used in drug carriers; and when used in vascular embolism , Good swelling can prevent the microcapsules from migrating in the blood vessels. In addition, the structure is stable, and the embolism can be more stable.

Detailed ways

The following specifically describes the present invention in combination with specific embodiments:

Example 1

3 grams of chitosan was dissolved in 97 grams of a 1% (w / w, mass percent concentration) acetic acid aqueous solution to form a 3% (w / w) chitosan solution. 3 grams of propylene glycol alginate was dissolved in 97 grams of water to form a 3% (w / w) solution of propylene glycol alginate. Mix the above chitosan solution with the propylene glycol alginate solution in a 500 ml beaker. The mixed solution was directly extruded into a 2% NaOH aqueous solution through a syringe to obtain a wet blended microcapsule. The wet microcapsules are washed with water and dried at 80 ° C to obtain dry blended microcapsules.

The wet-blended microcapsules of chitosan and propylene glycol alginate in Example 1 have a diameter of about 3000 microns, and a diameter of about 400 microns after drying. Take 1 g of dry blended microcapsules, immerse them in 40 ml of physiological saline solution (aqueous solution containing 0.9% sodium chloride), leave them at 37 ° C for 30 minutes, and measure the wet weight after taking out to 5.32 g. The hygroscopicity of the chitosan and propylene glycol alginate blended microcapsules prepared in Example 1 was 5.32 g / g.

Example 2

15 grams of chitosan was dissolved in 485 grams of a 1% w / w acetic acid aqueous solution to form a 3% w / w chitosan solution. 15 grams of propylene glycol alginate was dissolved in 485 grams of water to form a 3% w / w solution of propylene glycol alginate. In a 200 ml beaker, 100 g, 90 g, 75 g, 50 g, 25 g, and 10 g of the chitosan solution were mixed with 1 g, 10 g, 25 g, 50 g, 75 g, and 100 g of algae, respectively. The propylene glycol ester solution was mixed, and the obtained blend solution was extruded into a 4% NaOH aqueous solution under the action of a pulsed electrostatic field of 8 kV (pulse width 4 ms, frequency 180 Hz), to obtain a wet blended microcapsule . The wet microcapsules are washed with water and dried at 80 ° C to obtain dry blended microcapsules. The hygroscopicity of 7 samples was measured according to the method in Example 1. The results obtained are shown in Table 1 below.

Table 1

3% propylene glycol alginate (g)	100	75	50	25	10	1
3% Chitosan (g)	10	25	50	75	90	100
Wet particle size (micron)	635	560	525	500	485	450
Dry particle size (micron)	160	160	145	145	120	105
Moisture absorption (g / g)	10.5	9.2	8.1	6.3	4.5	1.36

From the data in Table 1, it can be seen that with the increase of the content of propylene glycol alginate in the blended material, the hygroscopicity of the blended microcapsules has improved significantly. On the one hand, the addition of propylene glycol alginate to chitosan can effectively improve the water absorption of the material; on the other hand, the addition of chitosan to the propylene glycol alginate can produce a crosslinked structure, thereby improving its wet stability. Since the two solutions can be mixed in any ratio during the preparation process, in actual use, an appropriate mass ratio of chitosan and propylene glycol alginate can be used to prepare microcapsules for blending with chitosan and propylene glycol alginate.

During the preparation of the blended microcapsules, the reaction between the amino group in the chitosan and the ester group in the propylene glycol alginate caused the two polymers to form a stable cross-linked structure. The chitosan and the propylene glycol alginate were blended. Microcapsules have high hygroscopic expansion and good structural stability, and can achieve good sustained-release properties when used in drug carriers. When used in vascular embolism, good expansion properties can prevent microcapsules in the blood vessels. Migration, combined with structural stability, can stabilize the embolism.

Example 3

2 grams of chitosan was dissolved in 98 grams of a 0.5% (w / w, mass percent concentration) acetic acid aqueous solution to form a 2% (w / w) chitosan solution. 4 g of propylene glycol alginate was dissolved in 96 g of water to form a 4% (w / w) propylene glycol alginate solution, and 0.5 g of bone morphogenetic protein (BMP-2) was added after complete dissolution. Mix the above chitosan solution with the propylene glycol alginate solution in a 500 ml beaker. The mixed solution was extruded into a 3% NaOH aqueous solution through a syringe under a high-voltage electrostatic field (voltage: 8kv; pulse width: 3ms; frequency: 100Hz) to obtain a wet-blended microcapsule with an average diameter of 200 μm.

Twenty-five male male rats of the same month were selected, and the drug-loaded microspheres were injected into the abdominal cavity of the rats. Four rats were sacrificed at 4h, 8h, 24h, 3 days, and 5 days after the neck was killed and taken out of the abdominal cavity. The microcapsules were blended and the amount of BMP-2 released was measured. The results showed that the BMP-2 release rate was 5.2% at 4 hours, the BMP-2 release rate was 18.6% at 8 hours, the BMP-2 release rate was 42.7% at 24 hours, and the BMP-2 release rate was 74.9% at 3 days. By 5 days, the BMP-2 release rate reached 98.5%.

This example demonstrates that the wet-blended microcapsules as a slow-release drug carrier have good sustained-controlled release capabilities, and have good biocompatibility and biosafety.

Example 4

5 grams of chitosan was dissolved in 98 grams of a 5% (w / w, mass percent concentration) acetic acid aqueous solution to form a 5% (w / w) chitosan solution. 5 grams of propylene glycol alginate was dissolved in 96 grams of water to form a 5% (w / w) propylene glycol alginate solution. Mix the above chitosan solution with the propylene glycol alginate solution in a beaker. The mixed solution was extruded into a 8% NaOH aqueous solution through a syringe under a high-voltage electrostatic field (voltage: 12 kv; pulse width: 6 ms; frequency: 350 Hz) to obtain a wet-blended microcapsule.

Using the prepared chitosan and propylene glycol alginate blended microcapsules as embolic substances and wet blended microcapsules as embolic substances, the embolic substance was injected or delivered into the target blood vessel through a catheter, so that the target site blood vessel Occlusion. Chitosan and propylene glycol alginate blended microcapsules achieve the purpose of treatment by blocking blood flow in the blood vessels and reducing blood supply to the lesion or a specific part of the body. The wet blended microcapsule has better embolization effect and higher targeting to specific tissues and organs.

Example 5

0.5 g of chitosan was dissolved in 98 g of a 5% (w / w, mass percent concentration) acetic acid aqueous solution to form a 0.5% (w / w) chitosan solution. 0.5 g of propylene glycol alginate was dissolved in 96 g of water to form a 0.5% (w / w) propylene glycol alginate solution. Mix the above chitosan solution with the propylene glycol alginate solution in a beaker. The mixed solution was extruded into a 5% aqueous NaOH solution through a syringe under a high-voltage electrostatic field (voltage: 1 kv; pulse width: 1 ms; frequency: 10 Hz) to obtain a wet-blended microcapsule.

The prepared chitosan and propylene glycol alginate blended microcapsules were applied to a sustained-release drug, and the chitosan and propylene glycol alginate blended microcapsules were used as a slow-release drug carrier, and chitosan and alginic acid were used. The propylene glycol ester blended microcapsules are combined with the drug to achieve the effect of sustained release of the drug. Using the wet-blended microcapsules as a slow-release drug carrier, the drug is slowly released in the body with a stable concentration, which improves the safety of the drug, while traditional drugs are released in large quantities within a short period of time, which causes the drug level in the serum to rapidly increase and the drug to peak The concentration decreases rapidly. The wet-blended microcapsules are harmless to the human body, have good biocompatibility, can be degraded, or can be completely excreted from the body. They have higher biological safety and are ideal for slow-release drug carriers.

Of course, the above description is not a limitation on the present invention, and the present invention is not limited to the above examples. Changes, modifications, additions or substitutions made by those skilled in the art within the scope of the present invention should also belong to the present invention. The scope of protection of the invention.

Claims (9)

1. A method for preparing chitosan and propylene glycol alginate blended microcapsules is characterized by adopting the following steps:

   The chitosan is dissolved with a 0.5% -5% acetic acid solution, the propylene glycol alginate is dissolved with water, and then the two solutions are mixed and squeezed into a 2-8% NaOH aqueous solution under a high-voltage electrostatic field to form a wet state. The blended microcapsules are washed and dried to obtain a dry blended microcapsule.
2. The method for preparing chitosan and propylene glycol alginate blended microcapsules according to claim 1, wherein the voltage of the high-voltage electrostatic field is 1-12kv, the pulse width is 1-6ms, and the frequency is 10-350Hz.
3. The method for preparing a chitosan and propylene glycol alginate blended microcapsule according to claim 2, wherein the voltage of the high-voltage electrostatic field is 8kv, the pulse width is 3ms, and the frequency is 100Hz.
4. The method for preparing chitosan and propylene glycol alginate blended microcapsules according to claim 1, wherein the chitosan is formed by dissolving the chitosan with an acetic acid solution with a concentration of 0.5-5% by mass. The mass percentage concentration of the solution is 0.5 to 5%, and the mass percentage concentration of the propylene glycol alginate solution formed by dissolving the propylene glycol alginate in water is 0.5 to 5%.
5. The method for preparing a blend of chitosan and propylene glycol alginate according to claim 4, wherein the weight ratio of the chitosan and the propylene glycol alginate is (1-10) :1.
6. Application of a chitosan and propylene glycol alginate blend microcapsule prepared by a method for preparing a chitosan and propylene glycol alginate blend microcapsule according to any one of claims 1 to 5 as an embolic substance .
7. The method for preparing chitosan and propylene glycol alginate blended microcapsules according to any one of claims 1 to 5 is prepared on a slow-release medicine. Applications.
8. The method for using chitosan and propylene glycol alginate blended microcapsules as an embolizing substance according to claim 6, wherein the wet blended microcapsules are used as an embolizing substance and injected into a target blood vessel through a catheter or The embolic material is sent in to occlude the blood vessels at the target location; thereby achieving the intended therapeutic purpose.
9. The method for applying chitosan and propylene glycol alginate blended microcapsules to a sustained-release drug according to claim 7, wherein the chitosan and propylene glycol alginate blended microcapsules are used as a slow-release drug A carrier, combining chitosan and propylene glycol alginate microcapsules with a drug to achieve the effect of sustained drug release.