CN1283350C - Method for preparing microcapsule by high-voltage electric field encystation and low-temperature extraction and solidification - Google Patents

Abstract

The present invention discloses a method for preparing a microcapsule by high-voltage electric field encystation and low-temperature extraction and solidification, which is characterized in that the method comprises the procedures: the mixed propanone liquid of core material and wall material passes through a microcapsule forming device of a high-voltage electric field; under the functions of electric field force added by the device, and a thruster, liquid balls with different particle diameters are made by adjusting electric field voltage and a liquid surface; the liquid balls are dropped in a liquid nitrogen container for freezing and solidifying the liquid balls to form a ball; the container is arranged in a low temperature environment at-60 DEG C to-90 DEG C, and the solid ball is slowly dissolved; then, propanone is carried away by an extractant so as to cause a polymer to generate deposition and cause a microcapsule to be solidified; ionized water is used for cleaning and centrifugation, and then freeze drying and storage are carried out to the microcapsule. The method has the actual effect that the method can prepare a microcapsule with regular shape, better dispersancy and higher encapsulation rate and medicine carrying capacity, and moreover, the method overcomes the defects of the low encapsulation rate, the poor dispersancy and easy agglomeration of the traditional preparing method of a microcapsule with biodegradability.

Description

High-voltage electric field encapsulation and low-temperature extraction and solidification to prepare microcapsules

technical field

The invention relates to a new process for preparing biodegradable sustained-release microcapsules, in particular to a method for preparing microcapsules by high-voltage electric field encapsulation, low-temperature extraction and solidification.

Background technique

Microencapsulation technology has been developed for decades. It has been found that microspheres made of drugs coated with wall materials through microencapsulation technology have the advantages of improving drug stability, achieving sustained or controlled release of drugs, and improving biocompatibility. However, most of the natural polymer wall materials discovered earlier cannot be degraded in the body and easily cause accumulation in the body. They are not suitable for intravenous injection and subcutaneous implantation, which limits the application of microcapsule products in the human body. In recent years, people have developed artificially synthesized biodegradable polymer wall materials, such as polylactic acid (PLA), polylactic acid-polyethylene glycol copolymer (PLA-PEG) and polylactic acid-polyglycolic acid copolymer (PLGA). )wait. They have the advantages of high chemical stability, can be degraded in vivo, and can be used for intravenous injection. Among them, PLA and PLGA have been approved by the US FDA Food and Drug Administration as drug release carriers.

Biodegradable polymer materials are difficult to prepare into microcapsules due to their high chemical stability and poor water solubility. At present, most of the biodegradable microcapsules of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) are prepared by emulsification dispersion method and phase separation method. The solvent evaporation method is a commonly used preparation method in the emulsification dispersion method, mainly including single emulsion method (O/W, O/O) and double emulsion method (W/O/W). The disadvantage of the single emulsion method is that it is sensitive to water-soluble drugs. The encapsulation rate is low, generally around 20%. The compound (double) emulsion method (W/O/W) is also a commonly used preparation method of PLGA microcapsules in recent years. It can effectively hinder the distribution of drugs into the continuous phase, thereby increasing the encapsulation efficiency. It is reported that the encapsulation efficiency of microcapsules prepared by double emulsion method can reach 40% to 70%. The double-emulsion method has gone one step further on the basis of the single-emulsion method, but it also has shortcomings: ①The sudden release of microcapsules is serious; ②The shape of the microcapsules is irregular, easy to aggregate, and the dispersion is not good; ③Add emulsification Agents and surfactants, protein drugs are easy to denature; ④The loss of drugs in the water phase still exists, and the encapsulation efficiency is general. In addition to the emulsification and dispersion method, the main preparation techniques also include phase separation (coagulation) method and spray drying method. The microcapsule particles prepared by the phase separation (coagulation) method are easy to agglomerate, which is difficult for practical production and application; and although the PLA and PLGA microcapsules can be successfully prepared by the spray drying method, the microcapsules will adhere to the spray-drying process during the preparation process. The inner wall of the container, which causes a large loss of product during the spray-drying process and agglomerates the product.

Contents of the invention

The purpose of the present invention is to overcome the problems existing in the prior art, and provide a method for preparing microcapsules by high-voltage electric field encapsulation, low-temperature extraction and solidification to prepare slow-release microcapsules of biodegradable materials. Combining the high-voltage electric field method with the low-temperature extraction method, a new process for preparing biodegradable microcapsules was constructed.

The technical scheme of the present invention is a method for preparing microcapsules by high-voltage electric field encapsulation and low-temperature extraction and solidification. The method steps are:

1. Suspend the core material in the acetone solution of the wall material with a concentration of 1% to 6% (W/V);

2. Pass the above suspension through the high-voltage electric field microcapsule molding device described in ZL00218100.2, under the action of the electric field force and propeller applied to the device, adjust the distance between the lower end of the syringe and the liquid nitrogen surface by adjusting the electric field voltage and the advancing speed of the syringe to make liquid balls of different particle sizes;

3. Drop the liquid ball into the container with alcohol extractant and -196°C liquid nitrogen in the device to freeze the liquid ball to form a ball;

4. Place the container in a low-temperature environment of -60°C to -90°C, and use the difference in freezing point between the alcohol extractant and acetone to make the extractant dissolve first, while the frozen ball of the acetone mixture dissolves slowly;

5. Then take away the acetone with an alcohol extractant, so that the polymer is deposited and the microcapsules are solidified;

6. After the solidification is completed, wash with deionized water, centrifuge, freeze-dry and store for testing.

The actual effect of this method is: this method has already dispersed the core wall material mixture into uniform microspheres before curing, and then slowly solidifies, so on the one hand, it will not be caused by liquid-liquid extraction. The high pressure of the microcapsules breaks away the microcapsule shell or produces large pores, resulting in severe burst release of the microspheres, low encapsulation efficiency, and low drug loading; Good property, no aggregation. No matter from which direction the polymer starts to deposit, microcapsules with regular shape and good dispersion can be prepared in principle. Compared with other methods such as phase separation coagulation method and double emulsion method, these characteristics have certain advantages, because these methods have higher requirements for the control of polymer sedimentation and viscosity conditions during the curing process and are not suitable for control, and the control is not easy. It caused severe sudden release of microcapsules, aggregation, encapsulation efficiency and drug loading decreased. And this method overcomes the defective of these methods. In addition, the preparation process of the method is carried out under anhydrous conditions, and for the embedding of hydrophilic protein substances, the encapsulation efficiency can have a relatively high level. The method operates in a low-temperature environment without adding emulsifiers and surfactants, and has advantages for heat-sensitive drugs such as polypeptide proteins.

Description of drawings

Fig. 1 is the schematic diagram of microcapsule forming device,

Fig. 2 is a flow chart of the method for preparing microcapsules by high-voltage electric field encapsulation and low-temperature extraction and solidification.

In Fig. 1, 1. High-voltage electrostatic field generator, 2. Positive pole of high-voltage generator, 3. Negative pole of high-voltage generator, 4. Syringe, 5. Propeller, 6. Support, 7. Liquid nitrogen, 8. Frozen micro balls, 9. frozen ethanol

Detailed ways

In conjunction with the accompanying drawings, the present invention will be further described in the embodiment prepared by insulin and poly(lactic-co-glycolic acid) copolymer with a mass ratio of 1:9:

1. According to the ratio of insulin: poly(lactic-co-glycolic acid) copolymer 1: 9, insulin is dissolved in 3.5% (W/V) poly(lactic-co-glycolic acid) copolymer acetone solution;

2. Take a 200mL plastic measuring cup, pour 20ml of absolute ethanol into the bottom, freeze it with liquid nitrogen at -196°C, add liquid nitrogen to the required liquid level, and pass the prepared insulin and PLGA suspension through The microcapsule forming device of high-voltage electric field, as shown in Figure 1, is prepared by adjusting a certain voltage (such as 3.3-3.6kV), liquid surface distance (25-35mm), and propulsion speed under the action of electric field force and propeller. liquid balls of different particle sizes.

3. Drop the liquid ball into the -196°C liquid nitrogen plastic measuring cup of the device to freeze the liquid ball into a solid ball.

4. Put the plastic measuring cup in a low-temperature environment of -88°C, using the difference in freezing point between ethanol and acetone (the freezing point of ethanol is -117.3°C, and that of acetone is -94.6°C), the ethanol extractant dissolves first, and the frozen acetone The mixed liquid globule dissolves slowly as it approaches the freezing point.

5. Then the acetone is taken away with ethanol extractant, so that the polymer is deposited, and the microcapsules are solidified, and the solidification time is 2 days.

6. After the solidification is completed, wash with deionized water, centrifuge, freeze-dry and store for testing.

It is known from experiments that when the electric field voltage is 3.4kV, the liquid surface distance is 35mm, and the advancing speed is 20mm/min, the particle size of the prepared insulin microcapsules is less than 200μm, the encapsulation rate is 83.2%, and the drug loading is 8.82%. The release time is 7 days, which can basically meet the needs of sustained-release preparations and solve the daily burden of frequent injections for diabetic patients.

Claims (1)

1. A high-voltage electric field encapsulation method for preparing microcapsules by low-temperature extraction and solidification, characterized in that the method steps are: (1) suspending the core material in the acetone solution of the wall material with a concentration of 1% to 6% (W/V); (2) Pass the above-mentioned suspension through the high-voltage electric field microcapsule forming device described in ZL00218100.2, under the action of the electric field force and the propeller applied to the device, by adjusting the electric field voltage, adjusting the distance between the lower end of the syringe and the liquid nitrogen liquid surface The distance and the speed of the syringe are used to make liquid balls of different particle sizes; (3) The liquid ball is dropped into the container of the alcohol extractant and -196°C liquid nitrogen in the device to freeze the liquid ball to form a ball; (4) Place the container in a low-temperature environment of -60°C to -90°C, and use the difference in freezing point between the alcohol extractant and acetone to make the extractant dissolve first, while the frozen ball of the acetone mixture dissolves slowly; (5) Acetone is then taken away with an alcohol extractant, so that the polymer is deposited, and the microcapsules are solidified; (6) After the solidification is completed, wash with deionized water, centrifuge, freeze-dry and store for testing.

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