KR102645357B1 - Method for manufacturing microparticle and microparticle manufactured by the same method - Google Patents

Abstract

According to an embodiment of the present invention, a method for manufacturing microparticles comprises the steps of: preparing a mold including an intaglio part; discharging droplets of a microparticle raw material solution to the intaglio part of the mold; pressing the microparticle raw material solution filled in the intaglio part; drying the microparticle raw material solution; and collecting microparticles molded in the shape of the intaglio part by drying the microparticle raw material solution. The droplet discharge step includes a multiple discharge step of dividing the total amount of the microparticle raw material solution supplied as one-time discharge into n (n is an integer of 2 or more) droplets and performing discharge.

Description

Micro particle manufacturing method and micro particles manufactured by the manufacturing method {METHOD FOR MANUFACTURING MICROPARTICLE AND MICROPARTICLE MANUFACTURED BY THE SAME METHOD}

The present invention relates to a method for manufacturing micro particles and micro particles produced by the method.

Drugs and bioactive substances are generally administered orally in tablet or capsule form, but many drugs cannot be effectively delivered using the above administration method alone for reasons such as being digested or absorbed in the gastrointestinal tract or lost through liver mechanisms. Additionally, some drugs cannot diffuse effectively across the intestinal mucosa. Additionally, patient compliance is also an issue. Another common technique for the delivery of drugs and bioactive substances is the use of conventional needles. While this method is more effective than oral administration, it has the problem of causing pain at the injection site, local damage to the skin, bleeding, and disease infection at the injection site.

To solve the problems of oral administration and subcutaneous injection, a transdermal administration method through a patch is used. Transdermal administration using a patch has fewer side effects, higher patient compliance, and makes it easier to maintain a constant blood concentration of the drug. As one of the transdermal administration methods described above, various microstructures including microneedles have been developed. Metals and various polymer materials were used as materials for microneedles. Recently, biodegradable polymer materials have been in the spotlight as a material for microneedles. These microneedles are manufactured in the form of a patch equipped with an adhesive sheet and used by attaching it to a desired area of the human body using an adhesive sheet. However, these microneedle products are manufactured in the form of patches and can only be used in limited areas of the human body. Furthermore, there is a problem in that the effectiveness is very low when the adhesive strength of the adhesive sheet is weak. As an alternative to patch-type microneedle products, technology for micro particles (or micro needle particles or micro spicules, hereinafter, the name of the product that is the subject of the present invention is unified as micro particles) has emerged.

As a prior art for manufacturing micro particles, Korean Patent Publication No. 10-2302311 (Title of the invention: Manufacturing method of microneedle-particles, Cosmetic product containing microneedle-particles manufactured by this manufacturing method, hereinafter referred to as " The first prior art"), Korean Patent Publication No. 10-2114979 (title of the invention: micro spicule, mold for manufacturing the same, and method for manufacturing the same, hereinafter referred to as the "second prior art")) will be referred to below. First, the first prior art is based on a manufacturing method called the blowing tensile method, which is widely known in the microstructure industry at the time of the filing date of the present invention. In the method of manufacturing micro particles by droplet extension, a viscous material is spotted on a sheet, another sheet is brought close to the viscous material to make contact with the viscous material, and the sheets are separated by a distance. The steps of stretching the viscous material, blowing the stretched viscous material to solidify the viscous material, and extracting and collecting micro particles formed on the sheet are sequentially performed. In the first prior art, in order to easily separate the micro particles formed on the sheet from the sheet, a blowing tensile process is performed by spotting a hydrophilic viscous material on a hydrophobic sheet made of polymer plastic such as PET, PC, PE, PU, PP, PS, etc. proceeded. The second prior art is based on a widely known molding method for manufacturing micro structures. The engraved mold used in the molding method can be prepared in a variety of ways. In the second prior art, a silicon embossed mold was produced by exposing a pattern on a silicon wafer and then bulk-etching, and nickel was added to this silicon embossed mold. After plating, pressure was applied to the heated polymer PP with a hot press to prepare an engraved mold. In the second prior art, as shown in FIG. 2, a solution was applied to an engraved mold to fill it, dried at room temperature, and then the micro particles were separated from the mold.

In the first prior art based on the blow tensile method, a method of spotting a hydrophilic viscous material on a hydrophobic plastic sheet is used, making it easy to separate the final product, micro particles, from the sheet, but maintaining adhesion between the sheet and the viscous material. Since little was done, the viscous material was not properly stretched during the stretching process, and microparticles with the desired structure were often not obtained. To solve this problem, a method of using a hydrophilic sheet or a water-soluble sheet instead of a hydrophobic sheet has emerged, but in this method, a separate process to weaken the adhesive force between the sheet and the micro particles must be performed to separate the micro particles from the sheet, thus increasing the cost. There was a problem of increasing time (see Korean Patent Publication No. 10-2504373). In the second prior art based on the molding method, there is a problem of insufficient filling of the solution in the engraved part of the intaglio mold, or the problem of drying without the air bubbles in the solution being discharged, creating a space due to the bubbles inside the micro particles, etc. There were frequent cases where micro particles of the desired structure were not obtained.

The present inventor(s) have devised a method for manufacturing micro particles that can efficiently produce micro particles that have a desired shape from the base to the tip and contain almost no air bubbles, based on the above-described molding method. did. The new manufacturing method of micro particles and specific characteristics of micro particles manufactured by this manufacturing method will be described later.

The purpose of the present invention is to provide an efficient production method of micro particles having a desired shape from the base to the tip, based on a molding method.

Additionally, the purpose of the present invention is to provide a method for producing micro particles that can remove most of the bubbles contained in the micro particle raw material solution filled in the mold intaglio during the production process.

In addition, in the present invention, in manufacturing a multi-stage microstructure in which a functional material, including a medicinal material, is located at the tip and other biodegradable materials are located at the base, it has a desired shape from the base to the tip and does not contain air bubbles. The purpose is to provide a method for producing micro particles that is excellent in terms of demonstrating functional effects due to transdermal injection of functional substances.

A micro particle manufacturing method according to an embodiment of the present invention includes preparing a mold including an engraved portion; discharging droplets of a micro particle raw material solution into the concave portion of the mold; applying pressure to the micro particle raw material solution filled in the concave portion; drying the micro particle raw material solution; It includes collecting micro particles molded into the shape of the concave portion by drying the micro particle raw material solution.

The droplet discharge step, the pressurization step, and the drying step are sequentially repeated once or multiple times.

When the droplet discharge step, the pressurization step, and the drying step are performed sequentially once, in the droplet discharge step, the total amount of the micro particle raw material solution supplied by one discharge is divided into n droplets (n is an integer of 2 or more). Perform multiple discharges.

When the droplet discharge step, the pressurization step, and the drying step are sequentially repeated multiple times, in the first droplet discharge step, a droplet of a relatively low-viscosity solution with a low polymer content is discharged to the tip of the intaglio portion, and in the second droplet discharge step, In the droplet discharge step, droplets of a relatively high viscosity solution with a high polymer content are discharged, and in the next droplet discharge step, the total amount of micro particle raw material solution supplied in one discharge is divided into n droplets (n is an integer of 2 or more). Perform multiple discharges.

The micro particle raw material solution may be composed only of biodegradable compositions.

Additionally, the pressurizing step and the drying step may be performed simultaneously within a chamber that performs pressurization and drying.

Additionally, in the mold preparation step, a mold including an engraved portion can be prepared by injection molding a thermoplastic resin.

Micro particles manufactured according to the above-described manufacturing method are included within the scope of the present invention.

In addition, additional components may be further included in the micro particle manufacturing method according to the present invention.

According to the present invention, an efficient production method of micro particles having a desired shape from the base to the tip can be provided, based on a molding method.

In addition, according to the present invention, a method for producing micro particles can be provided that can remove most of the bubbles contained in the micro particle raw material solution filled in the mold intaglio during the production process.

In addition, according to the present invention, in manufacturing a multi-stage microstructure in which functional materials, including medicinal materials, are located at the tip and other biodegradable materials are located at the base, bubbles are formed while having a desired shape from the base to the tip. Since it does not contain a micro particle, a method for producing excellent micro particles can be provided in terms of demonstrating functional effects due to transdermal injection of functional substances.

1 is a diagram conceptually showing the entire process of a micro particle manufacturing method according to an embodiment of the present invention.
Figure 2 is a photograph of a mold prepared through injection molding.
Figure 3 is a conceptual diagram to explain the concepts of one-shot ejection and multiple ejection by contrast.
Figure 4 is a diagram conceptually showing the filling pattern in the mold concave portion for one-shot discharge and multiple discharge.
Figure 5 is a photograph of liquid droplets ejected by a multiple ejection method into the concave part of a mold prepared by injection molding.
Figure 6 is a photograph of micro particles produced by one-shot discharging the micro particle raw material solution and pressurizing and drying in a pressure chamber.
Figures 7 and 8 are photographs taken of multi-stage micro particles test-produced according to another embodiment of the present invention, that is, the manufacturing method of multi-stage micro particles described above.

The embodiments described below are illustrative for the purpose of explaining the technical idea of the present disclosure, and the scope of the present disclosure is not limited to the embodiments or detailed descriptions presented below.

All technical and scientific terms used in this specification, unless otherwise defined, have meanings commonly understood by those skilled in the art to which this disclosure pertains, and all terms used in this specification are defined in this disclosure. It was selected for the purpose of explaining more clearly and was not selected to limit the scope of the present disclosure.

Expressions such as “comprising,” “comprising,” “having,” and the like used in this specification are open terms that imply the possibility of including other embodiments, unless otherwise stated in the phrase or sentence containing the expression. -ended terms).

Hereinafter, with reference to the attached drawings, preferred embodiments of the present disclosure will be described in detail so that those skilled in the art can easily implement them. In the accompanying drawings, identical or corresponding components are indicated by the same reference numerals, and in the description of the following embodiments, duplicate descriptions of identical or corresponding components may be omitted. However, even if descriptions of specific components are omitted in the description below, this does not mean that such components are not included in the embodiment.

<Overall process of micro particle manufacturing method according to an embodiment of the present invention>

1 is a diagram conceptually showing the entire process of a micro particle manufacturing method according to an embodiment of the present invention.

The first step is to prepare a mold whose end includes a concave portion. The second step is a step of discharging droplets of the micro particle raw material solution into the concave portion of the mold. The third step is to pressurize the micro particle raw material solution filled in the concave portion. The fourth step is drying the micro particle raw material solution. The fifth step is a step of collecting micro particles molded into the shape of the concave portion by drying the micro particle raw material solution.

To be described in more detail with reference to FIG. 1, in this example, a jig was used in which a total of 32 holes were formed in 8 columns and 4 rows into which the injection molded mold could be seated. A total of 32 injection molds were placed in these jigs. Afterwards, discharge was performed on individual molds using discharge equipment. After discharging of all molds was completed, the jig was mounted on a movable tray. One or more jigs can be mounted on the tray in any number. The tray equipped with the jig was moved to the pressurization chamber. In the pressurization chamber, as shown in the drawing, air injection and discharge occur simultaneously, and thus pressurization and drying processes can proceed simultaneously. The simultaneous progress of pressurization and drying in the pressurization chamber will be explained in more detail in the pressurization and drying steps described later. After the drying process was completed, the tray was moved outside the pressurization chamber, the mold was separated from each jig, and the micro particles molded in individual molds were collected. Various methods can be used to collect micro particles from individual molds, such as sucking them into a vacuum or collecting them after separating them from the mold by vibrating or hitting them. However, the scope of the present invention is limited to a specific micro particle collection method. It doesn't work. One of the key features of the overall process of the micro particle manufacturing method according to an embodiment of the present invention described above exists in the method of discharging droplets into the mold, which will be described later.

<Mold preparation step according to an embodiment of the present invention>

In the mold preparation step according to an embodiment of the present invention, any mold forming method widely known in the art at the time of the filing date of the present invention can be used. The mold material does not discriminate between metal and non-metal materials. The scope of the present invention is not limited to the use of a mold prepared in a specific manner or with a specific material, as long as an engraved part including a tip is provided to exercise the function of the micro particle. However, hereinafter, the case of using a thermoplastic material as a mold material will be explained. There are various ways to prepare molds from thermoplastic materials, examples include:

- Injection molding method of manufacturing a mold by heating a thermoplastic material to a molten state, injecting it into a mold, then cooling and detaching it from the mold.

- A thermo-compression molding method that forms an engraved part by applying heat to a press with an embossed part corresponding to the shape of the engraved part to be formed in a mold and then compressing the thermoplastic material.

- Spraying method in which thermoplastic material is sprayed and applied onto a mold with embossed parts, then dried and molded.

- Dipping method of dipping a mold with embossed parts into a solution containing a thermoplastic material and then drying it to form the mold.

- Other methods include processing an engraved part on a thermoplastic material using a blade or processing machine, or a method of providing a mold by processing an engraved part on a thermoplastic material using 3D printing.

Among the various mold molding methods described above, in this embodiment, a mold manufactured through injection molding method will be used. The present inventor(s) found that using a mold prepared through injection molding has an advantage in producing micro particles. The present applicant has described in detail the manufacturing method of a microneedle array using a mold prepared through injection molding in Patent Application No. 10-2021-0116881 (title of the invention: Microneedle array and manufacturing method thereof), and the Korean The content of the patent application specification shall be regarded as being set forth in its entirety herein.

Figure 2 is a photograph of a mold prepared through injection molding. In FIG. 2, reference numeral 10 indicates a mold prepared through injection molding, and reference numeral 11 indicates an engraved portion of the mold. Although it is not clearly visible from the drawing, the engraved portion 11 has a sharp end shape. The concave shape including the pointed end, that is, the tip, is a necessary element for the function of micro particles that penetrate the user's skin and biodegrade within it. The material of the mold 10 in FIG. 2 includes thermoplastic resins such as polyethylene terephthalate (PET), polyvinyl chloride (PVC), and polypropylene (PP), but is not limited thereto.

As of the filing date of the present invention, the industry that researches, produces, and sells microneedles or microparticles widely uses the heat compression method to prepare molds of thermoplastic materials for mass producing microneedles or microparticles. Using a mold prepared by the injection molding method has the advantage that the height of individual engravings is formed very precisely without deviation compared to the thermocompression method. Furthermore, there is an advantage in that many engraved parts can be placed in a smaller area, thereby increasing the efficiency of mass production of micro particles. In thermocompression molding, the minimum gap required for deformation is required between the intaglio parts, whereas in injection molding, there is no such limitation regarding the spacing between the intaglio parts, so the intaglio part can be brought into close contact with each other as much as possible, and this allows for the amount of space placed per unit area. The number of engraved parts can be increased compared to the heat pressing method.

<Liquid droplet discharge step according to an embodiment of the present invention>

In this step, the object to be discharged toward the concave part of the mold is a raw material solution of micro particles, and this raw material solution contains a biodegradable composition. Functional substances may be mixed into these biodegradable compositions.

Biodegradable compositions include hyaluronic acid and its salts, polyvinylpyrrolidone, polyvinyl alcohol, cellulose polymer, dextran, gelatin, glycerin, polyethylene glycol, polysorbate, propylene glycol, povidone, and carbomer ( carbomer, gum ghatti, guar gum, glucomannan, glucosamine, dammer resin, rennet casein, locust bean gum, microfibrillated cellulose, psyllium seed. psyllium seed gum, xanthan gum, arabino galactan, gum arabic, alginic acid, gelatin, gellan gum, carrageenan, karaya gum, curdlan, chitosan, Chitin, tara gum, tamarind gum, tragacanth gum, furcelleran, pectin, or pullulan may be used. Functional substances are substances that penetrate into the skin and perform specific functions such as pharmacological effects, such as chemical drugs, protein drugs, peptide drugs, nucleic acid molecules and nanoparticles for gene therapy, and cosmetic ingredients (e.g., anti-wrinkle agents, skin aging inhibitors, and skin whitening agent), etc.

It has already been mentioned that one of the key features of the entire process of the micro particle manufacturing method according to an embodiment of the present invention is the method of discharging droplets into the mold. As a first step in explaining this characteristic droplet dispensing method, the concepts of one-shot dispensing and multi-shot dispensing will be explained with reference to FIG. 3.

Figure 3 is a conceptual diagram to explain the concepts of one-shot ejection and multiple ejection by contrast.

Figure 3 conceptually shows a dispenser for discharging droplets of a raw material solution of micro particles and a nozzle provided at the end of the dispenser to finally discharge the droplets. Below the dispenser and nozzle, a mold mounted on a jig is positioned with the engraved portion facing upward. The nozzle of the dispenser is aligned with the concave part of the mold. One-shot discharge refers to a method of discharging the total amount of the raw material solution of micro particles to be discharged as one droplet in one discharge. On the other hand, multiple discharge refers to a method of discharging the total amount of the raw material solution of micro particles to be discharged by dividing it into several droplets in one discharge. For example, when spraying a micro particle raw material solution with a total capacity of 10 mg from the nozzle of the dispenser in one discharge, one-shot discharge is performed as one droplet of 10 mg capacity, and 10 droplets of 1 mg capacity are discharged. Executing discharge is multiple discharge. One of the features of the present invention is that the above-described multiple ejection is included at least once in the entire ejection process. Hereinafter, the advantages of such multiple ejection over one-shot ejection will be explained.

Figure 4 is a diagram conceptually showing the filling pattern in the mold concave portion for one-shot discharge and multiple discharge.

In the conceptual diagram of FIG. 4, the left side assumes the case where one 10 mg droplet is ejected. The right side assumes that 10 droplets of 1 mg are ejected. Referring to this conceptual diagram, two major advantages of multiple discharge compared to one-shot discharge can be mentioned in relation to the performance of filling the concave part of the mold.

The first is excellent tip filling performance. While the concave part of the mold is filled with a gas such as air, droplets of the micro particle raw material solution are discharged into the concave part. At this time, the gas present in the concave part of the mold acts as an obstacle to the liquid droplets penetrating deep into the concave part. However, when the size of a single droplet is small, it can relatively easily push out the gas present in the engraved part and penetrate deeply. On the other hand, when the size of a single droplet is large, the droplet itself tends to seal the engraved part, so it cannot penetrate deeply while pushing out the gas in the engraved part. In this way, even before the droplets of the engraved part are pressed downward in the subsequent step, the case where multiple discharges are performed and each droplet is small in size is compared to the case where the droplet is discharged in one shot and the size of each droplet is relatively large, so that the tip of the lowermost part of the engraved part is It is excellent in terms of filling performance. Even in the pressurization process after liquid droplet discharge, if the size of one droplet is large, it is difficult to completely discharge the gas present at the tip of the mold intaglio even if downward pressure is applied during the pressurization process. This is because the tip of the final product, the micro particle, is not sharp but has a blunt shape. This can lead to the determination of defective products from a production management perspective.

Second, the defect rate is reduced due to bubbles in the droplet itself. When a liquid droplet is discharged, the liquid droplet itself contains air bubbles and is discharged into the engraved portion. Although it would be desirable for the liquid droplets to be discharged without air bubbles, it is nearly impossible to control the liquid droplets so that they do not contain air bubbles even using the best dispensers currently available commercially. However, as shown in the conceptual diagram of FIG. 4, small droplets contain relatively small bubbles. Large droplets contain relatively large bubbles. In one embodiment of the present invention, drying is performed simultaneously with pressurization in a pressure chamber. When downward pressure is applied to the liquid droplets filled in the concave part of the mold due to the pressure applied from the pressurization chamber, the space filled with gas inside the concave part is As the liquid droplets fill, the gas inside the engraved part is pushed out, and air bubbles contained in the droplets themselves can also be removed. However, relatively large bubbles contained in large droplets are difficult to remove from the droplets during the pressurization process. The remaining air bubbles that are not removed during the pressurizing and drying process exist as internal cavities in the final product, micro particles. Micro particles with large internal cavities are considered defective products from a production management perspective. Relatively small-sized bubbles contained in small-sized droplets are not only easy to remove in the pressurization process, but even if some small-sized bubbles are not removed and coexist within the final product, the microparticles, the presence of some small cavities is a problem in production management. From this point of view, it may not lead to a judgment of defective product.

Figure 5 is a photograph of liquid droplets ejected by a multiple ejection method into the concave part of a mold prepared by injection molding.

In the example of Figure 5, a total of 21 mg of micro particle solution was divided into 12 droplets and discharged (21 mg, 12 shots). As can be seen from the photo in FIG. 5, the 12 liquid droplets that were discharged multiple times piled up starting from the lowest tip of the concave part of the mold, achieving filling of the entire concave part, including the tip. In addition, from the photo in FIG. 5, it can be seen that the droplet protrudes in a roughly semicircular shape over the mold intaglio (since the droplet shrinks as water, a solvent, is removed during the drying process, the intaglio part is (exceeding filling is carried out), small bubbles present in this area can be confirmed. Bubbles of this small size can be easily removed in the subsequent pressurization step, and even if some of them are dried without being removed, they do not adversely affect the quality of the final product, the micro particles.

<Pressurizing and drying steps according to an embodiment of the present invention>

Referring again to FIG. 1, the pressurizing and drying steps according to an embodiment of the present invention will be described. Referring to FIG. 1, after the micro particle raw material solution is filled into the concave part of the mold, the jig loaded with a large number of molds is moved to the pressurization chamber. When the jig loaded with the mold completes its movement to the pressurization chamber, the chamber is shielded. While the pressurization chamber is shielded, air is injected through the inlet of the pressurization chamber, thereby increasing the pressure of the pressurization chamber. In this state, the micro particle raw material solution filled in the mold concave part is subjected to downward pressure due to the gas pressure inside the pressurizing chamber, and at this time, the fine bubbles in the raw material solution are removed as they escape from the raw material solution. In addition, the raw material solution is pressured downward toward the bottom of the concave part, that is, the tip, and the gas present in the concave part, including the tip, is discharged to the outside, causing the microparticle raw material solution to more densely fill the concave part of the mold. At the same time, air is discharged through the outlet of the pressurization chamber. A convection phenomenon occurs within the pressurization chamber due to the simultaneous injection of air through the inlet of the pressurization chamber and the discharge of air through the outlet. In Figure 1, this convection phenomenon is indicated by a blue arrow. Convection of air within the pressurization chamber dries the raw material solution filled in the mold depression.

Assuming that the pressure of the air injected through the inlet of the pressurization chamber is X bar and the pressure of the air discharged through the outlet of the pressurization chamber is Y bar, the pressure inside the pressurization chamber It could be more than that. Air injection and air discharge are performed simultaneously in the pressurization chamber, but the internal pressure of the pressurization chamber is maintained at 1.5 bar or more, preferably 2 bar or more, so that the raw material solution is deposited in the mold concave portion by downward pressure of the micro particle raw material solution. It is possible to more densely fill the mold engraving with the raw material solution while removing the gas occupying the space, and in this process, the drying of the raw material solution can proceed smoothly at the same time. If the pressure inside the pressurizing chamber is maintained below a certain value, the performance of discharging gas within the mold concave portion to fill the concave portion more densely and releasing air bubbles from the raw material solution may be reduced.

In the pressurization and drying step according to an embodiment of the present invention, pressurization and drying are carried out simultaneously in the above-described manner, so the process is simplified and the process time is shortened compared to the case where pressurization and drying are performed as separate processes, thereby increasing process efficiency. This has the effect of lowering the possibility of contamination of the raw material solution by reducing exposure to the external environment of the raw material solution filled in the mold intaglio during the manufacturing process.

The advantageous effects of the method for producing micro particles according to an embodiment of the present invention should not be understood as the result of the organic combination of the processes of each step, rather than being achieved by any one step of the multiple step processes described above. In this respect, the present inventor(s), as one of the key features of the present invention, discharges the mold concave portion using one-shot discharge instead of the multiple discharge method described above, and pressurizes while maintaining the pressure of the pressurization chamber above the standard pressure. and drying were carried out simultaneously to experimentally produce micro particles. Figure 6 is a photograph of micro particles that are the result of such experimental production. In the pilot production of Figure 6, 16 mg of the microparticle raw material solution was discharged in one shot, and was then pressurized and dried while maintaining 6 bar in a pressure chamber.

Referring to FIG. 6, various types of micro particles, which are defective products, can be identified. First, the defect occurrence pattern indicated by the white dotted circle will be explained. Here, the micro particles were dried in a state where a large amount of gas trapped in the concave part of the mold during one-shot ejection could not escape to the outside despite going through the pressurization process, and the micro particle solution overflowed the concave part of the mold by the volume. The solution that overflowed the concave part of the mold invaded the adjacent micro particle area, producing a defective product where adjacent micro particles were connected to each other. This solution overflow phenomenon may occur when bubbles within the droplet burst during the discharge process. Next, the defect occurrence pattern indicated by the red circle will be explained. Here, the bubbles present inside one large droplet discharged in one shot could not escape from the droplet of the raw material solution before drying of the raw material solution was completed. As a result, defective products with large bubbles present inside the molded micro particles were manufactured. Lastly, the defect occurrence pattern indicated by the blue circle will be explained. Here, it is confirmed that the tip of the micro particle is blunt rather than sharp. The gas present at the tip of the mold intaglio was pushed out and drying was completed without the micro particle raw material solution penetrating to the tip, producing a defective product.

Unlike the various defective products confirmed in the photograph of FIG. 6, the micro particles produced through all the processes described in the patent claims of the present invention have the desired shape from the base to the tip, contain almost no bubbles inside, and are contained in the raw material solution. The biodegradable polymer material contained in appears to be uniformly distributed throughout the entire volume. By comparing the photograph of the defective product in FIG. 6 with the photograph of the microparticles manufactured according to the manufacturing method of the present invention in FIGS. 7 and 8, the advantageous effects of the manufacturing method according to the present invention can be clearly understood.

<Micro particle collection step according to an embodiment of the present invention>

After the above-described pressure drying process is completed, the tray can be moved outside the pressure chamber and the molds can be separated from each jig to collect micro particles molded in individual molds. Various methods can be used to collect micro particles from individual molds, such as sucking them into a vacuum or collecting them after separating them from the mold by vibrating or hitting them. However, the scope of the present invention is limited to a specific micro particle collection method. It doesn't work.

The collected microparticles are biodegradable and hydrophilic, so they easily decompose when stored in liquid containing water or exposed to moisture, but can be stored for a long time in a container containing oil. When applying micro particles collected and stored in an oil container to the skin, the micro particles along with a certain amount of oil can be removed from the container and applied to the skin or applied to the skin together with cream-type cosmetics. When micro particles mixed with cream-type cosmetics are rubbed and spread on the skin area to be applied, the micro particles penetrate the skin, allowing the biodegradable or functional substances that make up the target micro particles to penetrate into the body through the skin.

In addition, as described above, according to one embodiment of the present invention, a mold in which a thermoplastic resin is injection molded is used, and this feature provides an additional embodiment with respect to the method of collecting micro particles. Injection moldings of thermoplastic resins themselves are excellent packaging containers. After the pressure drying process is completed, the micro particles are accommodated in the individual engravings of the mold. If the upper surface of the engravings of the mold is sealed and packaged in this state, it can be a micro particle packaging product ready to be shipped to the market. By modifying the shape of the mold to suit this purpose, it would be possible to complete sealed packaging by adding oil to improve storage while the micro particles are accommodated in individual engraved parts. In this way, packaging with the micro particles positioned in the concave portion of the mold rather than removing the micro particles from the mold and packaging them separately should be understood to be included in the scope of collection of micro particles described in the patent claims of the present invention. .

<Multi-stage micro particle manufacturing method according to another embodiment of the present invention>

In the above-described example, micro particles were manufactured by sequentially going through i) a mold preparation step, ii) a droplet discharge step of the micro particle raw material solution, iii) a pressurizing and drying step, and iv) a micro particle collection step. In general, if the micro particles are made of the same material evenly distributed throughout, it is effective to manufacture micro particles using this method. For example, in the case of micro particles used for cosmetic purposes, the entire structure of the micro particles may be formed of a single polymer hyaluronic acid structure. In the production of such micro particles, the manufacturing method of the above-described embodiment may be applied.

However, the present inventor(s) have mentioned functional polymer materials as polymer materials included in the raw material solution of micro particles. Functional polymer materials include various chemical drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, and nanoparticle cosmetic ingredients (e.g., anti-wrinkle agents, skin aging inhibitors, and skin whitening agents). When manufacturing micro particles containing such a functional polymer material, the functional polymer material is concentrated and distributed at the tip of the particle that penetrates the skin, and the base excluding the tip of the particle is biodegradable to complete and maintain the shape of the particle. It may be advantageous to have polymeric materials predominate. This embodiment is particularly useful in the production of micro particles with such a multi-stage structure.

The present inventor(s) have designed a manufacturing method particularly suitable for manufacturing micro particles with a multi-stage structure by utilizing each of the steps unique to the present invention described above. In this manufacturing method, preparing a mold whose end includes a concave portion, discharging a droplet of a micro particle raw material solution into the concave portion of the mold, pressurizing and drying the micro particle raw material solution filled in the concave portion. In terms of passing through, it is the same as the method of manufacturing a microstructure of a single material described above. However, in this embodiment, the liquid droplet discharge step and the pressurization and drying steps are sequentially repeated multiple times. Then, in the first droplet discharge step, droplets of a relatively low-viscosity solution with a low polymer content are discharged at the tip of the intaglio part, and in the second droplet discharge step, droplets of a relatively high-viscosity solution with a high polymer content are discharged. In addition, in the next liquid droplet discharge step, multiple discharges are performed in which the total amount of micro particle raw material solution supplied in one discharge is divided into several droplets. As in the method of manufacturing a micro structure of a single material, the micro particles that have completed the final round of liquid droplet discharge, pressurization, and drying through the above steps go through a collection step to finally complete the production of the micro particles.

Figure 7 is a photograph taken of multi-stage micro particles test-produced according to another embodiment of the present invention described above, that is, the method of manufacturing multi-stage micro particles.

The conditions applied by the present inventor(s) in this test production are summarized in the following table.

1st round 2nd round discharge area tip base Number of droplets per discharge One 9 Discharge amount 1.5 mg 20mg Solution composition and weight percent 5% HA+10% trehalose+2% food coloring red No. 40 35% PVP (polyvinylpyrrolidone) +10% PVA (polyvinyl alcohol) Pressurized pressure after discharge 6 bar 6 bar

In this test production, red food coloring was used as a material representing the functional material to check whether the functional material was concentrated at the tip and distributed well. As summarized in the table above, during the first droplet discharge, a total of 1.5 mg of solution was discharged as a single droplet. The reason why single droplet discharge, that is, one-shot discharge, was applied for the first droplet discharge is because a very small amount of 1.5 mg was used as a functional material solution to fill the tip. During the second discharge, a total of 20 mg of solution was multiple discharged in the form of 9 droplets, and the capacity of one droplet during this second discharge was approximately 2.22 mg. That is, the capacity of one droplet in the first droplet discharge is less than the capacity of one droplet in the second time multiple discharges are performed, even though it is one-shot discharged. However, the scope of the present invention should not be construed as limited to the fact that the first round of liquid droplet discharge is one-shot discharge in multi-stage discharge. In some cases, the capacity can be relatively large even in a single discharge of the functional material, and in this case, a multi-stage discharge method that is advantageous for filling the tip of the mold intaglio can be applied.

An important distinction between one-time discharge and more-time discharge is the viscosity of the solution being discharged. In the first droplet discharge step, discharge is performed with a relatively low-viscosity solution with a low polymer content, while in the second droplet discharge step, discharge is performed with a relatively high-viscosity solution with a high polymer content.

Referring to the table above, in the first discharge, 5% hyaluronic acid, 10% trehalose, and 2% food coloring red No. 40 were included in the solution to be discharged as a polymer material, and the weight percent of water as a solvent at this time was 73. %am. During the second discharge, 35% of PVP (polyvinylpyrrolidone) and 10% of PVA (polyvinyl alcohol) were included in the solution to be discharged as a polymer material, and at this time, the weight percent of water as a solvent was 55%. It can be seen that the solution viscosity during the first discharge is relatively much lower compared to the second discharge.

The advantages achieved by adopting this configuration are clear. This is advantageous in performing thorough filling of the tip, which is the narrowest area among the concave portions of the mold. The space occupied by the tip is very small compared to the volume of the entire micro particle, but if the tip is not formed into a shape with a sharp angle as originally designed, the micro particles penetrate the skin and become deeply embedded in the skin, preventing the functional substances contained therein from being properly delivered to the skin. This can significantly reduce the performance of all micro particles. A discharge solution with relatively low viscosity is not only advantageous in filling the tip of the concave part of the mold to the end, but is also advantageous in terms of releasing air bubbles contained in the discharge solution. Bubbles contained in a droplet of a low-viscosity solution can be relatively easily separated from the droplet by pressure from the top in a pressurization process following discharge.

On the other hand, the space of the concave part after the tip has already been filled by one-time discharge, pressurization and drying is relatively wide, so even if the viscosity is increased (even if the content % of biodegradable polymer material is increased), there is no gap under the condition of multiple discharges. There is no problem in filling the concave part of the mold. Furthermore, the relatively small volumetric shrinkage that inevitably occurs as the solvent component is removed during the drying process is advantageous for producing micro particles of a desired shape without wasting space in the concave part of the mold. This is the reason why the raw material solution has a relatively high viscosity during the next discharge, which is performed after the tip of the mold intaglio is formed through the first discharge and the subsequent pressure drying process. When discharging the second shot, a large amount of droplets of a relatively high viscosity solution are discharged, so for the reasons explained in detail above, multiple discharge is more advantageous than one-shot discharge. If the discharge of the second ash for the base composition, which accounts for most of the micro particle volume, is performed as a one-shot discharge, large air bubbles are generated in one large droplet and the viscosity is high, making it more difficult to discharge air bubbles, which may cause defects. In general, the functional polymer material contained in the solution discharged from the tip is relatively expensive, so if a defect occurs at the base when the filling of the functional polymer material into the tip is completed, the expensive functional material will be wasted. Performing the base discharge of the relatively high viscosity material in multiple discharges can be evaluated as a particularly important matter in this embodiment.

Looking at the photo in Figure 8, it will be easy to confirm the excellence of the manufacturing method unique to the present invention. In the photograph of FIG. 8, micro particles in which red and light green food coloring representing the functional material are distributed intensively at the tip are confirmed, and the sharp angle of the tip is confirmed in all micro particles. In addition, from the micro particles photographed with the tip facing upward, it can be seen that a total of six angled sides are intact and intact, taking on a perfect star shape when viewed from above. The microparticles shown in FIG. 8 that the present inventor(s) test-produced are very small in size, barely visible to the naked eye, with a total height of about 300 micrometers (0.3 mm) from the tip to the base. The fact that a structure of this size can be manufactured with this level of accuracy without any error depending on the shape of the mold's intaglio while manufacturing a biodegradable polymer material is solely due to the unique manufacturing method of the present invention described above.

In this example, a case where the types of polymer materials included in the solution for one discharge and the polymer materials included in the solution for subsequent discharges are different was described, but the scope of the present invention is not necessarily limited thereto. Even if the same type of polymer material is included in the solution at each time of discharge, the liquid droplet discharge, pressurization, and drying process is repeated multiple times as described in this example, and in the first droplet discharge step, the polymer material with a relatively low polymer content is used. Performing the process of discharging droplets of a low-viscosity solution and multiple discharging droplets of a relatively high-viscosity solution with a high polymer content in the second droplet discharge step is more effective than performing only one cycle of discharging, pressurizing, and drying. It may be more advantageous to manufacture micro particles of a desired shape that are tightly filled and bubble-free. However, in this case, discharging, pressurizing, and drying are repeated multiple times, which may result in the disadvantage of increasing the process time.

In the above, the present disclosure has been described through specific details such as specific components and limited embodiments and drawings, but this is only provided to facilitate a more general understanding of the present disclosure, and the present disclosure is not limited to the above embodiments. , a person skilled in the art to which this disclosure pertains will be able to make various modifications and variations from this description.

Accordingly, the spirit of the present disclosure should not be limited to the above-described embodiments, and the claims described below as well as any equivalent or equivalent modifications thereto should be construed as falling within the scope of the spirit of the present disclosure.

Claims (5)

preparing a mold including an engraved portion;
discharging droplets of a micro particle raw material solution into the concave portion of the mold;
applying pressure to the micro particle raw material solution filled in the concave portion;
drying the micro particle raw material solution;
Comprising the step of collecting micro particles molded into the shape of the concave portion by drying the micro particle raw material solution,
The droplet discharge step, the pressurizing step, and the drying step are sequentially repeated once or multiple times,
When the droplet discharge step, the pressurization step, and the drying step are sequentially performed once, in the droplet discharge step, the total amount of the micro particle raw material solution supplied by one discharge is divided into n droplets (n is an integer of 2 or more). Perform multiple ejections that
When the droplet discharge step, the pressurization step, and the drying step are sequentially repeated multiple times, in the first droplet discharge step, a droplet of a relatively low-viscosity solution with a low polymer content is discharged to the tip of the intaglio portion, and in the second droplet discharge step, In the droplet discharge step, droplets of a relatively high viscosity solution with a high polymer content are discharged, and in the next droplet discharge step, the total amount of micro particle raw material solution supplied in one discharge is divided into n droplets (n is an integer of 2 or more). Performing multiple discharges,
Micro particle manufacturing method.
According to paragraph 1,
The micro particle raw material solution consists only of biodegradable composition,
Micro particle manufacturing method.
According to paragraph 2,
The pressurizing step and the drying step are performed simultaneously in a chamber that performs pressurization and drying.
Micro particle manufacturing method.
According to paragraph 3,
In the mold preparation step, a mold including an engraved portion is prepared by injection molding a thermoplastic resin.
Micro particle manufacturing method.
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