KR101429477B1 - Drug carrier manufactured by using ink-jet printing process and preparation method thereof - Google Patents

Abstract

The present invention relates to a three-dimensional polymer drug delivery system prepared by inkjet printing of a polymer ink prepared by mixing a biocompatible polymer, a drug, and an organic solvent, and a method for producing the same. The present invention provides a drug delivery system that can be manufactured in various three-dimensional forms by inkjet printing using a polymer ink prepared to control drug release, and a method of manufacturing the drug delivery system. When the drug delivery system is used, And the amount of drug delivery can be precisely controlled.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a polymeric drug delivery system and a method of manufacturing the same. 2. Description of the Related Art [0002]

The present invention relates to a polymeric drug delivery system manufactured using an inkjet printing method and a method of manufacturing the same. More particularly, the present invention relates to a polymeric drug delivery system using a three-dimensional To a polymer drug delivery system and a manufacturing method thereof.

Drug delivery technology using controlled release technology began in 1970 and has developed rapidly, and numerous products are currently on the market or under development.

Polymeric drug delivery systems can be subdivided into sustained-release formulations such as polymer-drug conjugates and sustained-release formulations of drugs using polymeric nano / microparticles and polymeric micelles. Drug delivery devices include drug delivery devices using semiconductor chips, patch formulations using chemotherapy wafers, micro-needles, and implant systems using osmotic membranes. In order for the drug to function effectively in vivo, the drug's body concentration must be maintained within a therapeutic range for a certain period of time. Excessive amounts of the drug in the body will be toxic, and in too small doses, the therapeutic effect will not appear. The drug delivery system plays a role in regulating it.

Particularly, the field of application of nanoparticles for drug delivery, which is one of the fields of recent interest, focuses not only on the size of the particles itself but also on the function of the particles. Typical methods of preparing nanoparticles for drug delivery include polymeric nanoparticles using self-emulsification diffusion method, polymer nanoparticles using a complex reaction of ionic polymers, and block copolymers having hydrophilic / lipophilic groups Synthesis of star-like polymers using nanoparticles and dendrimers through micelle formation, and methods for preparing drug carriers using nanoparticles in the form of hydrophilic capsules using phospholipids, nanosomes, spray drying, lithography, etc. have.

However, the above-mentioned method of preparing a drug delivery vehicle has limitations in producing various shapes, so that it is mostly made into a spherical shape, and the drug content is low, the function of the drug delivery system should be controlled with limited conditions such as size and chemical composition, There is a problem that the kind of drug that can be carried by the drug is limited or the drug is concentrated at the beginning of the release, the manufacturing process is complicated, the process time is long, and the loss of the material is large.

DISCLOSURE OF THE INVENTION The present inventors have repeatedly studied to solve the above-mentioned problems associated with the conventional method of manufacturing a drug delivery system. As a result, in the step of preparing the polymer ink by mixing the biocompatible polymer, the drug and the organic solvent, the amount of ink, the number of ink droplets, and the concentration of the added drug and polymer required for printing one drug carrier are calculated in advance, In the case of preparing a drug delivery vehicle in a three-dimensional form by using the inkjet printing method of the polymer ink thus prepared, the drug delivery vehicle thus prepared is capable of tailor-controlled drug release according to the patient, And that the amount of the drug can be precisely controlled, thereby completing the present invention.

Reference to Korean Patent No. 10-0949850, No. 10-0517253, and the like can be referred to regarding the related art.

It is an object of the present invention to provide a drug delivery system in which the drug release can be controlled in a customized manner according to the patient and the drug delivery amount is accurately controlled.

Another object of the present invention is to provide a drug delivery device which can be manufactured in various shape and size uniformly by various inkjet printing methods using a polymer ink prepared so as to control drug release, and has a simple process, a low defect rate, And to provide a method for manufacturing such a high-molecular drug delivery system.

In order to accomplish the above object, the present invention provides a method for preparing a polymeric drug delivery system using the inkjet printing method, comprising: S1) preparing a polymer ink by mixing a biocompatible polymer, a drug, and an organic solvent; (S2) injecting the polymer ink into a printer cartridge and mounting the polymer ink into an inkjet printer; And connecting a computer programmed to produce the drug carrier of the desired shape to the inkjet printer, and forming a drug carrier by inkjet printing a polymer ink on the substrate (S3).

The biocompatible polymer may be at least one selected from the group consisting of polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid- Poly-L-glutamic acid, poly-L-leucine, poly-L-lysine, polysaccharides, amylose, hydroxyethyl starch, polyvinylpyrrolidone, Poly (? -Hydroxy acid), polyglycolide, polylactide, poly (? -Malic acid), poly (? - hydroxyacid) Poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4- Dioxane-7-one), poly (ester-carbonate), poly (glycolide-1,3-dioxane- Poly (amide esters), polyphenylsipeptides, poly (alpha -cyano), poly (diisocyanates), poly (sebacic anhydride), polyorthoesters, polycarbonates, poly Acrylate), poly (ethyl- alpha -cyanoacrylate), and polyvinyl alcohol, or copolymers thereof.

The organic solvent may be at least one selected from the group consisting of tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethylsulfoxide, butanol, isopropanol, isobutyl alcohol, tetrabutyl alcohol, acetic acid, 1,4-dioxane, toluene, And a mixed solution of two or more kinds selected from the group consisting of hydrogen chloride, dimethylformamide, and the like.

In step S1, the polymer ink may be prepared by previously calculating the amount of ink, the number of droplets of the ink, and the concentration of the drug and the biocompatible polymer necessary for inkjet printing of the drug carrier to be produced.

The polymer ink may be prepared by adjusting the viscosity, the surface tension, and the contact angle so that a drug delivery system can be formed in a predetermined form.

The inkjet printing can be performed by the computer in which the image file in the form of the drug carrier to be manufactured in step S3 is programmed to be inkjet printed.

In the step S3, the drug carrier may be formed by printing a polymer ink onto a substrate and laminating the polymer ink in a three-dimensional form.

The three-dimensional shape may be a three-dimensional shape selected from the group consisting of a circle, a lattice pattern, a honeycomb, a ring, a rod, a square, a star and a triangle.

The step of preparing the substrate by O ₂ plasma surface treatment before forming the drug carrier by the ink jet printing method in the step S 3.

In order to accomplish the above object, the polymer drug delivery system of the present invention is formed by inkjet printing a polymer ink prepared by mixing a biocompatible polymer, a drug, and an organic solvent.

Wherein the biocompatible polymer is selected from the group consisting of polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid- Poly-L-lysine, poly-L-lysine, polysaccharides, amylose, hydroxyethyl starch, polyoxyethylene stearate, polyoxyethylene stearate, (? -Hydroxy acid), poly (? -Hydroxy acid), polyglycolide, polylactide, poly (? -Malic acid), poly Poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4-dioxane) (Ester-carbonate), poly (glycolide-1,3-dioxane-2-one), polyanhydride Poly (amide esters), polyphenylsipeptides, poly (alpha -cyano), poly (diisocyanates), poly (sebacic anhydride), polyorthoesters, polycarbonates, poly Acrylate), poly (ethyl- alpha -cyanoacrylate), and polyvinyl alcohol, or copolymers thereof.

The organic solvent may be at least one selected from the group consisting of tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethylsulfoxide, butanol, isopropanol, isobutyl alcohol, tetrabutyl alcohol, acetic acid, 1,4-dioxane, toluene, And dimethylformamide, or a mixed solution of two or more thereof.

The polymer ink may be prepared by adjusting the amount of ink, the number of droplets of ink, and the concentration of drug and biocompatible polymer according to a drug delivery vehicle to be produced.

The polymer ink may be prepared by adjusting the viscosity, the surface tension, and the contact angle so that a drug delivery system can be formed in a predetermined form.

The polymer drug delivery system can be controlled by adjusting the amount of ink, the number of droplets of the ink, and the concentration of the drug and the biocompatible polymer.

The present invention provides a drug delivery system that can be manufactured in various three-dimensional forms by inkjet printing using a polymer ink prepared so as to control drug release. Thus, when the drug delivery system is used, Not only can the drug delivery amount be accurately controlled, but also the patient's pain can be alleviated by increasing the efficiency of drug administration.

The present invention also provides a method of manufacturing a polymer drug delivery system using an inkjet printing method, thereby making it possible to manufacture various drug carriers of various three-dimensional shapes uniformly in shape and size, A drug delivery vehicle can be produced. In addition, since the process of the present invention is carried out at room temperature, the drug delivery vehicle can be manufactured using a small amount of ink and drug without damaging the biological activity of the biocompatible polymer contained in the polymer ink.

FIG. 1 schematically shows a step of preparing a polymeric drug delivery system using the inkjet printing method of the present invention.
2 schematically shows a method of manufacturing various types of drug carriers on one substrate using an inkjet printer according to an embodiment of the present invention.
3 is a photograph of drug carriers prepared according to Example 1 of the present invention.
4 is a photograph of drug carriers prepared according to Example 2 of the present invention.
FIG. 5 is a graph showing the results of three-dimensional structure analysis of drug carriers prepared according to Example 1 of the present invention. FIG.
6 is a graph showing a result of measurement of release rate of a fluorescent dye of drug carriers prepared according to Example 1 of the present invention.
FIG. 7 is an SEM image showing a process of hydrolyzing a cyclic drug carrier prepared in Example 1 of the present invention in PBS. FIG.
FIG. 8 is a graph showing the cumulative amount of release of the drug carrier prepared according to Example 1 of the present invention against the time square root in PBS. FIG.
FIG. 9 is a graph showing the drug release rate of a drug delivery vehicle manufactured according to Example 3 of the present invention. FIG.
10 is an SEM image showing a process of hydrolyzing a drug carrier prepared according to Example 3 of the present invention in PBS.
FIG. 11 is a graph showing the cumulative amount of release of the drug carrier prepared according to Example 3 of the present invention against the time square root in PBS. FIG.
12 is a graph showing cytotoxicity according to drug concentration of a drug delivery vehicle prepared according to Example 3 of the present invention.

Hereinafter, a method for producing a polymer drug carrier using the inkjet printing method according to the present invention will be described in detail.

First, a biodegradable polymer, a drug, and an organic solvent are mixed to prepare a polymer ink (step S1).

The biocompatible polymer contained in the polymer ink uses a polymer having excellent biocompatibility and biodegradability as a carrier for supporting a drug.

Biocompatible polymers well known in the art may be used without limitation. For example, biocompatible polymers that can be used in the present invention include poly 竜 -caprolactone (PCL), poly (lactic acid) (PLA); Poly-L-lactide (PLLA), poly-D, L-lactide (PDLLA), poly (glycolic acid) Lactic-co-glycolic acid (PLGA), poly (glycolic acid) (PG), poly (lactide-co-glycolic acid) (PTMC), poly-β-hydroxybutyrate (PHB), poly succinimide (PSI), polyamino acid-derived polymers, poly- L-glutamic acid, poly-L-leucine, poly-L-lysine, polysaccharides, amylose, Hydroxyethylstarch, dextran, alginic acids, chitin, polyesters, poly (? -Hydroxyalkanoate), poly (? - hydroxyalkanoate) (? -hydroxy acid) (pol y (? -hydroxy acids); Polyglycolide, polylactide, poly (a-malic acids), poly (omega -hydroxy acids), poly- poly (ε-caprolactone), poly (β-hydroxyalkanoate), poly (ester-ether), poly (ε-caprolactone) 1,4-dioxane-2-one), poly (1,4-dioxan-7-one) 1,3-dioxane-2-one), poly (ester-carbonate), poly (glycolide-1,3-dioxane- ), Polyanhydride, poly (sebacic anhydride), polyorthoester, polycarbonate, poly (1,3-dioxane-2- Poly (amide ester), polydepsipeptide, poly (alpha -cyanoacrylate) (poly (1,3-dioxane-2-one) (? -cyanoacryl ate), poly (ethyl-alpha-cyanoacrylate), polyvinyl alcohol, or the like can be used alone or in combination.

In the present invention, the drug contained in the polymer ink is not limited, and a solid drug or a liquid drug can be used.

As the organic solvent capable of preparing the polymer ink by dissolving the biocompatible polymer and the drug described above, any of them can be used as long as it can dissolve the biocompatible polymer and the polymer according to the kind of the drug to produce the polymer ink. Examples of the solvent include tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethylsulfoxide, butanol, isopropanol, isobutyl alcohol, tetrabutyl alcohol, acetic acid, 1,4-dioxane, toluene, , Dimethylformamide, etc. may be used alone or in combination, but the present invention is not limited thereto.

In the process of preparing the polymer ink, it is important to preliminarily calculate the amount of ink, the number of droplets of the ink, and the concentration of the drug and the biocompatible polymer necessary for inkjet printing of the drug carrier to be produced.

The amount of ink, the number of droplets of the ink, and the concentration of the drug and the biocompatible polymer are calculated in advance by using the inkjet printing method to prepare the polymer ink, so that the drug release rate and the amount of drug to be administered Can be adjusted.

The polymer ink is prepared by adjusting the viscosity of the polymer ink, the surface tension thereof, and the contact angle between the substrate and the ink so as to match the injectable physical properties of the polymer ink so that a drug delivery vehicle can be formed in a desired form.

More specifically, the viscosity of the polymer ink can be controlled according to the amount of the polymer. In the case of polymers, viscosity tends to increase rapidly, so it is necessary to control them. Although the amount (concentration) of the polymer varies depending on the characteristics of the ink, the range of the viscosity is relatively similar. The surface tension can be controlled by varying the composition of the solvent. The solvent having a high surface tension and the solvent having a low surface tension can be properly mixed and controlled. Since the contact angle is the original value of the substrate and the ink, the resolution can be adjusted during printing through the contact angle without adjusting the contact angle separately. Adjusting the resolution is the same as setting the position where the next ink drops after one ink drop has dropped. As described above, the viscosity, surface tension, and contact angle of the polymer ink should be set well to obtain a desired pattern precisely.

Next, the polymer ink is injected into the printer cartridge and then mounted on the inkjet printer (step S2).

The process of injecting the polymer ink prepared according to the above-described method into the inkjet printer cartridge and then mounting it on the printer can be easily performed by a person having ordinary skill in the art to which the present invention pertains, so a detailed description thereof will be omitted .

As the printer that can be used in the present invention, an ink jet printer can be used, and there is no particular limitation.

Finally, a computer programmed to manufacture the drug carrier of the desired shape is connected to the ink jet printer, and then the polymer ink is ink-printed on the substrate to form a drug carrier (step S3).

The substrate that can be used in the present invention may be a plate or film produced by using a polymer such as a slide glass, a paper, a silicon wafer, a polyimide (PI), a polyethylene terephthalate (PET), a polystyrene And can be used without limitation as long as it is capable of printing a polymer ink.

In one embodiment of the present invention, the surface energy of the substrate can be adjusted in order to prepare the substrate in a state suitable for preparing a drug carrier by inkjet printing. For example, a slide glass to be subjected to inkjet printing may be prepared in a state suitable for printing by O ₂ plasma surface treatment.

In step S3, a computer programmed to be inkjet-printed as an image file (for example, a bitmap image file) in the form of a drug carrier is connected to an inkjet printer, and inkjet printing of the polymer ink on the substrate is performed to laminate the desired three- A drug delivery vehicle can be produced.

In the present invention, the drug delivery system may be a circle, a grid, a honeycomb, a ring, a rod, a square, a star, a triangle, , And the like. However, the present invention is not limited thereto and may be manufactured in various forms.

According to the present invention, when a three-dimensional drug delivery device is manufactured by precise calculation by a computer program and inkjet printing by a lamination method, shape, size, height, etc. can be uniformly manufactured. Various forms of drug delivery can be printed at one time (see Figure 2).

In step S3, the process of forming a drug carrier by inkjet printing of a polymer ink is performed at room temperature, so that a drug carrier can be produced without impairing the biological activity of the biocompatible polymer.

The present invention also provides a polymeric drug delivery system formed by inkjet printing of a polymer ink prepared by mixing a biocompatible polymer, a drug, and an organic solvent, and can be manufactured according to the above-described manufacturing method.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention. Such variations and modifications are intended to be within the scope of the appended claims.

Polymer ink was prepared by dissolving polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA) and fluorescent dye in dimethylacetamide (DMAc), and the temperature was raised to 40 to 50 ° C at the time of dissolution. A polymer ink was prepared using a fluorescent dye instead of a drug.

Upon completion of the dissolution, viscosity and surface tension of the polymer ink were measured to confirm that they were within the appropriate range. The appropriate range depends on the experimental value because the characteristics are different for each polymer ink. The viscosity and the surface tension suitable for use in the printing system constituted in this experiment were in the range of 3 to 20 cps in viscosity and 20 dynes / cm or more in the surface tension in the case of the ink comprising a fluorescent dye and a polymer.

Thereafter, the drug delivery vehicle is introduced into the chamber by a circle, a grid, a honeycomb, a ring, a rod, a square, a star and a triangle. The bitmap image to be printed was made and the surface area of each image and the amount of ink required were calculated as shown in Table 1 below. Table 2 shows the amounts of polymer inks and fluorescent dyes used for each drug delivery system before printing the drug delivery system in which the concentration of the fluorescent dye and the number of layers are different.

The method for producing a polymeric drug delivery system using the inkjet printing method of the present invention can produce a drug delivery system using a small amount of a polymer ink and a drug and accurately calculate the amount of a material to be used in advance. Various types of drug carriers as shown in FIG. 3 were prepared by inkjet printing on a slide glass using the polymer ink thus prepared.

The polymer ink was prepared by dissolving polylactic acid-glycolic acid copolymer (molecular weight: 27,000) and fluorescent dye (FITC, fluorescein isothiocyanate) polymerized in the ratio of lactic acid: glycolic acid = 7: 3 in dimethylacetamide (DMAc) The temperature was raised to 40 to 50 占 폚. At this time, the concentration of the polylactic acid-glycolic acid copolymer was 100 mg / mL, and the concentration of the fluorescent dye was 100 mg / mL.

Various types of drug carriers were prepared by inkjet printing on a slide glass in the same manner as in Example 1, except that the polymer ink thus prepared was used in a lamination number of 30.

A fluorescence image of the drug carrier prepared according to Example 2 is shown in Fig.

As shown in FIG. 4, by printing the ink thus prepared on an ink-jet printer, a complex patterned drug delivery system could be uniformly produced.

Test Example  One: Example  3-D structure analysis of drug carriers prepared according to

The different types of drug carriers prepared according to Example 1 were photographed with a nanoview to analyze the three-dimensional structure. The results are shown in FIGS. 5 (a) and (b).

4, the diameters of the different types of drug carriers were measured to be 330 to 750 mu m and the height of the drug carriers to be about 6 mu m. The height of the drug carrier in a simple form such as a circle, a ring, a rectangle, But the bitmap image and the error were less printed.

Test Example  2: Bitmap image and In the example  Comparison of size of prepared drug carriers

The drug delivery materials of round, lattice pattern, honeycomb, annular, rod, square, star, and triangle prepared in the above Examples are compared with bitmap images used for manufacturing the drug carriers.

Referring to Table 3, each of the different types of drug delivery devices ink-jet printed using a bitmap image according to the present invention was printed with a length of some form of about 100 to 106% It can be seen that it is similarly printed. From this, it can be seen that when the polymeric drug delivery system is manufactured using the inkjet printing method according to the present invention, the drug delivery system can be manufactured by printing the drug delivery system in a desired form without material loss or complicated process.

Test Example  3: Example  1 < / RTI > Between carriers  Height, surface area and volume measurements

The height, top surface area and volume of the drug carriers prepared in the examples were measured and are shown in Table 4 below.

As shown in Table 4, the drug carriers prepared in the examples showed large upper surface area in the order of honeycomb, lattice pattern, annular shape, square shape, star shape, bar shape, circle shape and triangle shape, It can be seen that the difference is not large by the surface area difference.

Test Example  4: Drug release rate analysis of drug carriers

6 (a) and 6 (b), fluorescence dye release rates were measured for each of the round, lattice pattern, honeycomb, annular, rod, square, star and triangular drug carriers prepared in Example 1 Respectively. In this embodiment, since the fluorescent dye is used instead of the drug, the fluorescence dye release rate means the actual drug release rate. FIG. 6 (a) is a graph showing the release rate of a fluorescent dye to drug carriers prepared under the condition that the concentration of the fluorescent dye is 3 mg / ml and the number of laminations is 10 in the example. FIG. 6 (b) FIG. 5 is a graph illustrating the release rate of a fluorescent dye to drug carriers prepared under the condition that the concentration of the fluorescent dye is 10 mg / mL and the number of the laminate is 20 in the examples. FIG. Fluorescent dye release rates were calculated by summing the results of the 80 minute release measurements after confirming release and degradation for a total of 25 days after the drug carriers were immersed in phosphate buffer solution.

6 (a) and 6 (b), it can be seen that the release rate of the fluorescent dye is fast in the order of honeycomb, annular, lattice pattern, star, square, bar, triangle, . 6 (a) and 5 (b) are similar to each other, it can be seen that the specific mechanism is involved in the release rate, and it can be seen that the sequence in which the release rate is high and the order in which the surface area is large are very similar have. In addition, although the total volume of the drug delivery system and the amount of the staining agent are similar to each other, the release rate differs depending on the form of the drug delivery system, and a portion of the drug delivery system, such as a honeycomb, ring, The larger the structure, the faster the release rate. Taken together, these results indicate that the drug delivery rate can be controlled by controlling the form of the drug delivery system.

The cyclic drug delivery system prepared in Example 1 was immersed in PBS (Phosphate Buffered Saline) for 25 days to observe the hydrolysis process. In this process, after 14 days of immersion in the cyclic drug delivery vehicle, phosphate buffer solution before immersion in PBS, the drug delivery vehicle was photographed at 25 days after immersion in the drug delivery vehicle and phosphate buffer solution, , (b) and (c).

According to FIG. 7, pores were observed on the surface from the 14th day after immersing the cyclic drug carrier in the phosphate buffer solution, and the pores of the surface became larger and fell off on the 25th day.

Test Example  5: Example  Measurement of drug release constant of drug carriers prepared according to

The drug carriers prepared in Example 1 used the Higuchi model of the following formula for the release rate constants of the honeycomb, lattice, annular, star, square, bar, round, And the results are shown in Fig.

[Mathematical Expression]

Q = Kt ^1/2

Where Q is the partial drug release, K is the kinetic constant, and t is the release time.

Referring to FIG. 7, it can be seen that other types of drug carriers exhibit linearity and conform to the Higuchi model. Thus, in FIG. 7, the increase in the cumulative release amount with respect to the square root of the time indicates a linear relationship, which means that the drug release from the drug delivery system of the present invention is a controlled release.

Example 3 relates to a method for producing a polymer drug carrier containing an actual drug, that is, Paclitaxel (PTX), which is an anticancer drug.

A polymer ink was prepared by dissolving polylactic acid-glycolic acid copolymer (100 mg / mL) and paclitaxel (10 mg / mL) in dimethylacetamide. The ink had a physical viscosity of 5.99 cps at 25 캜, a surface tension of 35.40 dynes / cm.

Thereafter, a bitmap image was printed to print the drug carrier in a circle, a grid, a honeycomb, and a ring, and was printed on a slide glass. At this time, the printing condition was maintained at a firing voltage of 20 to 23 V, a frequency of 5 kHz, and a temperature of the printer nozzle and plate of 28 to 31 ° C. Also, the number of laminated layers was set to 30 to prepare a polymer drug delivery system.

The physical properties of the polymeric drug delivery vehicle prepared by the above method are shown in Table 5 below.

Shape PTX loading capacity (μg) Weight (μg) Height (μm) Volume (μm ³ ) Total surface area (μm ² ) Relative surface area circle 0.34 6.5 28 3,357,288 235,123 1.00 Lattice pattern 0.34 6.5 25 3,010,000 398,800 1.69 Honeycomb 0.32 6.0 23 3,378,033 579,740 2.46 Ring 0.34 6.5 25 3,477,864 367,405 1.56

The printed polymeric drug delivery system was shaped with a Nano view (High accuracy non-contact surface profiler).

According to Table 5, by the type of the drug delivery system, the amount of PTX loading and the weight of the carrier were the same or similar. Also, the volume of the drug delivery vehicle was greater or smaller within a range of about 10%.

In contrast, the total surface area of the drug delivery system showed a large difference by type, and the surface area was broad in the order of honeycomb, lattice, ring, and circular. Particularly, it was confirmed that the honeycomb type having many holes and the complex shape had a wider surface area of about 2.46 times than the circular shape, and a wider surface area of about 1.56 to 1.69 times than the circular pattern of the grid pattern and the ring shape.

Test Example  6: Example  The drug release rate by type of polymeric drug delivery system according to

200 mL of the same type of drug carrier and 5 mL of PBS (pH 7.4) containing 0.1% of polyoxyethylene sorbitan monooleate (trade name Tween 80) as an emulsifier were placed in the same test tube and samples were taken at regular intervals. At this time, the test tubes were allowed to move at a speed of 50 rpm in 37 ° C water. After taking the sample, 5 mL of PBS containing 0.1% tween 80 was replaced to take the next sample.

The flow rate of the PTX drug was determined by high performance liquid chromatography (HPLC) and UV detector. The UV wavelength was 205 nm, the flow rate was 1.0 mL / min, the mobile phase was 50:50 ratio .

A graph of drug release rate according to Test Example 6 is shown in Figs. 9A and 9B. Here, FIG. 9A shows cumulative discharge amounts in days, and FIG. 9B shows initial bursts in the graph of FIG. 9A for the first 0 to 6 hours.

According to Figs. 9A and 9B, on the first day, an initial burst occurred due to the PTX release on the surface of the drug delivery vehicle, and PTX was gradually released from the second day.

According to the form of the drug delivery system, in the case of the honeycomb type, almost 100% of PTX was released on the 6th day, 80% of the lattice pattern and the ring pattern and 60% of the round pattern were released. The larger the surface area, the larger the contact area with PBS, and thus the faster the release rate.

10 is an SEM image showing a state in which the drug carrier prepared according to Example 3 is decomposed with time.

According to FIG. 10, in 'Day 0', the state of the drug carrier before the decomposition test can be confirmed on the substrate. On the second day, the hydrolysis reaction was observed in the PBS, and the degradation of the drug carriers was significantly progressed. Particularly, it was observed that the pattern almost disappeared in the plaid pattern.

On the 4th day, the drug carriers were deformed by morphological distortion. Subsequently, on day 6, the morphology changed to such an extent that the original shape could not be recognized, and the decomposition proceeded further. At this time, the drug carriers of the grid pattern, honeycomb, and ring except for the circular shape occasionally broke. As in the above decomposition rate graph, it was confirmed that the decomposition of the circular drug carrier was the slowest in the form.

Test Example  7: Example  Measure drug release constants of drug carriers prepared according to

The drug carriers prepared in Example 3 were measured for release rate constants of drug delivery vehicles of circular, lattice pattern, honeycomb, and ring by using the Higuchi model of the equation shown in Test Example 5 The results are shown in Fig.

According to Fig. 11, graphs of other types of drug carriers show linearity and correspond to the Higuchi model, indicating that drug release from the drug delivery vehicle prepared according to Example 3 of the present invention is a controlled release type do.

Test Example  8: Example  Lt; RTI ID = 0.0 > in vitro < / RTI > In vitro ) Cytotoxicity test

Cell cytotoxicity was measured by WST assay for 48 hours.

DMEM and HeLa cells containing 10% FBS and 1% P / S were added to wells of a 24-well plate at 1 × 10 ⁴ , and cells were cultured in a cell culture incubator for 24 hours. After the incubation, the drug carriers prepared according to Example 3 were added in different numbers, that is, the cells were cultured for a predetermined time.

After reaching a predetermined time, the WST reagent was added to the wells and incubated for 1 hour in a cell incubator. 100 μL of the supernatant was collected and placed in a well of a 96-well plate. OD of the WST was measured at 440 nm using a microspectrophotometer Optical Density) values were measured.

A graph of the relationship between drug concentration and cell viability according to Test Example 8 is shown in Fig.

According to FIG. 12, it was confirmed that as the number of loaded drug carriers increases, that is, the drug concentration increases, the cytotoxicity increases and the cell survival rate decreases.

During 48 hours, there was no significant difference in cytotoxicity due to PTX concentration change in the range of 785 ~ 3925nM. However, when the PTX concentration was increased to 7850 nM, the cell viability and toxicity were greatly increased.

These results indicate that PTX is continuously released from the drug delivery system and its release affects cytotoxicity, that is, cell survival rate.

Claims (15)

(S1) mixing a biocompatible polymer, a drug, and an organic solvent to prepare a polymer ink;
(S2) injecting the polymer ink into a printer cartridge and mounting the polymer ink into an inkjet printer; And
(S3) connecting a computer programmed to produce a drug carrier of a desired shape to the inkjet printer, and then forming a drug carrier by inkjet printing a polymer ink on the substrate,
In the step S3, the polymer ink is laminated 10 to 30 times to form a drug carrier in a three-dimensional form having a predetermined thickness or more,
Characterized in that the polymer ink is manufactured such that the viscosity of the polymer ink is in the range of 3 to 20 cps and the surface tension is 20 dynes / cm or more so that the drug carrier can be formed in a three- (JP) METHOD FOR PREPARING POLYMER DRUG TRANSDUCER USING INKJET PRINTING METHOD.
The method according to claim 1,
Wherein the biocompatible polymer is selected from the group consisting of polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid- Poly-L-lysine, poly-L-lysine, polysaccharides, amylose, hydroxyethyl starch, polyoxyethylene stearate, polyoxyethylene stearate, (? -Hydroxy acid), poly (? -Hydroxy acid), polyglycolide, polylactide, poly (? -Malic acid), poly Poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4-dioxane) (Ester-carbonate), poly (glycolide-1,3-dioxane-2-one), polyanhydride Poly (amide esters), polyphenylsipeptides, poly (alpha -cyano), poly (diisocyanates), poly (sebacic anhydride), polyorthoesters, polycarbonates, poly Acrylate), poly (ethyl-alpha-cyanoacrylate), and polyvinyl alcohol, or a copolymer thereof. The method of manufacturing a polymer drug carrier using the ink-jet printing method.
The method according to claim 1,
The organic solvent may be at least one selected from the group consisting of tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethylsulfoxide, butanol, isopropanol, isobutyl alcohol, tetrabutyl alcohol, acetic acid, 1,4-dioxane, toluene, And dimethylformamide, or a mixed solution of at least two selected from the group consisting of dimethylformamide, and dimethylformamide.
The method according to claim 1,
In the step S1, the polymer ink is prepared by previously calculating the amount of ink, the number of droplets of the ink, and the concentration of the drug and the biocompatible polymer necessary for inkjet printing of the drug carrier to be produced. ≪ / RTI >
delete The method according to claim 1,
Wherein the inkjet printing is performed by a computer programmed to perform an inkjet printing of an image file in the form of a drug carrier to be manufactured in step S3.
delete The method according to claim 1,
Wherein the three-dimensional shape is a three-dimensional shape selected from the group consisting of a circle, a grid pattern, a honeycomb, a ring, a rod, a rectangle, a star and a triangle.
The method according to claim 1,
The method of manufacturing a polymeric drug delivery system using the inkjet printing method according to claim 1, further comprising the step of preparing a substrate by O ₂ plasma surface treatment before forming the drug delivery system by the ink jet printing method.
The polymeric drug delivery system according to claim 1, wherein the polymeric drug carrier is a three-dimensional form having a thickness of at least a predetermined thickness laminated with a polymer ink containing a biocompatible polymer and a drug and an organic solvent.
The method of claim 10,
Wherein the biocompatible polymer is selected from the group consisting of polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid- Poly-L-lysine, poly-L-lysine, polysaccharides, amylose, hydroxyethyl starch, polyoxyethylene stearate, polyoxyethylene stearate, (? -Hydroxy acid), poly (? -Hydroxy acid), polyglycolide, polylactide, poly (? -Malic acid), poly Poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4-dioxane) (Ester-carbonate), poly (glycolide-1,3-dioxane-2-one), polyanhydride Poly (amide esters), polyphenylsipeptides, poly (alpha -cyano), poly (diisocyanates), poly (sebacic anhydride), polyorthoesters, polycarbonates, poly Acrylate), poly (ethyl-alpha-cyanoacrylate), and polyvinyl alcohol, or a copolymer thereof.
The method of claim 10,
The organic solvent may be at least one selected from the group consisting of tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethylsulfoxide, butanol, isopropanol, isobutyl alcohol, tetrabutyl alcohol, acetic acid, 1,4-dioxane, toluene, And dimethylformamide, or a mixture of two or more thereof.
The method of claim 10,
Wherein the polymer ink is prepared by adjusting the amount of ink, the number of droplets of the ink, and the concentration of the drug and the biocompatible polymer according to the drug delivery vehicle to be produced.
delete The method of claim 10,
Wherein the polymeric drug delivery vehicle is prepared in a three-dimensional form having controlled specific surface area, thereby controlling the drug release amount and release rate.

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