KR20120028848A - Drug carrier manufactured by using ink-jet printing process and preparation method thereof - Google Patents

Abstract

PURPOSE: A polymer drug delivery system of three dimensional shape and a method for preparing the same are provided to control drug release. CONSTITUTION: A method for manufacturing a polymer drug delivery system by inkjet printing method comprises: a step of mixing biocompatible polymers, drug, and organic solvent to prepare polymer ink; a step of injecting the polymer ink to a printer cartridge and mounting the cartridge to an inkjet printer; and a step of performing inkjet printing of polymer ink on a substrate. The organic solvent includes tetrahydrofuran, dimethyl aceteamide, dimethyl formamide, chloroform, dimethyl sulfoxide, butanol, isopropanol, isobutayl alcohol, tetra butyl alcohol, acetic acid, 1,4-dioxane, toluene, or dimethyl formamide.

Description

Polymer drug carrier prepared using the inkjet printing method and a method for manufacturing the same {DRUG CARRIER MANUFACTURED BY USING INK-JET PRINTING PROCESS AND PREPARATION METHOD THEREOF}

The present invention relates to a polymer drug carrier prepared using an inkjet printing method and a method for manufacturing the same, and more particularly, to a three-dimensional form prepared by inkjet printing a polymer ink prepared by mixing a biocompatible polymer, a drug and an organic solvent. The present invention relates to a polymer drug carrier and a method for preparing the same.

Drug delivery technology using controlled release technology began in 1970 and has undergone rapid development, with numerous products now on the market or under development.

Drug delivery systems using polymers can be subdivided into long-term sustained-release formulations such as polymer-drug conjugates and sustained-release formulations of drugs using polymer nano / micro particles and polymer micelles. As drug delivery devices, drug delivery devices using semiconductor chips, chemotherapy wafers, patch preparations using microneedles, micro-needles, and implant systems using osmosis membranes have been developed. In order for the drug to function effectively in vivo, the body's concentration of the drug must be maintained within the therapeutic range for a certain period of time. If the drug is present in the body excessively, it becomes toxic, and in too small amount, there is no therapeutic effect, and the drug delivery system plays a role in controlling it.

In particular, the scope of application of the nanoparticles for drug delivery, which is one of the fields of recent interest, is focused on research on not only the size of the particles themselves but also the high functionality of the particles. Representative methods of manufacturing nanoparticles for drug delivery include polymeric nanoparticles using a self-emulsifying diffusion method, polymeric nanoparticles using a complex reaction of ionic polymers, block copolymers having hydrophilic / lipophilic groups, and the like. Synthesis of nanoparticles through micelle formation, star-like polymers using dendrimers, and hydrophilic capsule-type nano liposomes using phospholipids, spray drying, lithography, etc. have.

However, the method of manufacturing the above-described drug carrier has a limitation in manufacturing it in various shapes, so most of them are manufactured in a spherical shape, so that the drug content is low, the size, the chemical composition of the drug carrier must be controlled under limited conditions, manufacturing method Depending on the type of drug that can be supported is limited or the drug is released intensively at the beginning of the release, the manufacturing process is complicated and the process takes a lot of time, such as a large loss of material.

The present inventors have repeatedly studied to solve the problems related to the conventional method for producing a drug carrier. As a result, in the step of preparing a polymer ink by mixing a biocompatible polymer, a drug, and an organic solvent, the amount of ink required for printing one drug carrier, the number of ink drops, and the concentration of the added drug and the polymer are calculated in advance. In the case of manufacturing a drug carrier in a three-dimensional form using the inkjet printing method of the polymer ink prepared as described above, the drug carrier prepared according to the drug release can be adjusted according to the patient, and finally delivered It has been found that the amount of drug can be precisely controlled to complete the present invention.

For matters related to the prior art, Korean Patent Registration Nos. 10-0949850 and 10-0517253 may be referred to.

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug delivery system in which drug release can be adjusted according to a patient and drug delivery amount is precisely controlled.

It is another object of the present invention to prepare a variety of three-dimensional drug carriers in uniform shape and size by inkjet printing method using a polymer ink prepared to control drug release, the process is simple, low defect rate and reproducibility It is to provide a method for producing this high polymer drug carrier.

Method for producing a polymer drug carrier using the inkjet printing method of the present invention for achieving the above object comprises the steps of preparing a polymer ink by mixing a biocompatible polymer, drug and an organic solvent (S1); Injecting the polymer ink into a printer cartridge and mounting the ink to a inkjet printer (S2); And (S3) forming a drug carrier by connecting a computer programmed to manufacture a drug carrier of a desired shape with the inkjet printer and then inkjet printing a polymer ink on a substrate.

The biocompatible polymer is polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid-glycolic acid copolymer, polyglycolic acid , Polytrimethylene carbonate, polybetahydroxybutyl acid, polysuccinimide, polyamino acid-derived polymer, poly-L-glutamic acid, poly-L-leucine, poly-L-lysine, polysaccharide, amylose, hydroxyethyl starch , Dextran, alginic acid, chitin, polyester, poly (β-hydroxyalkanoate), poly (α-hydroxy acid), polyglycolide, polylactide, poly (α-malic acid), poly (ω- Hydroxy acid), poly-ε-caprolactone, poly (β-hydroxyalkanoate), poly (ester-ether), poly (1,4-dioxane-2-membered), poly (1,4- Dioxane-7-membered), poly (ester-carbonate), poly (glycolide-1,3-dioxane-2-membered), polyanhi Ride, poly (seba anhydride), polyorthoester, polycarbonate, poly (1,3-dioxane-2-membered), poly (amide ester), polydepsipeptide, poly (α-cyano Acrylates), poly (ethyl-α-cyanoacrylates), and polyvinyl alcohols, alone or in combination thereof.

The organic solvent is tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethyl sulfoxide, butanol, isopropanol, isobutyl alcohol, tetra butyl alcohol, acetic acid, 1,4-dioxane, toluene, ortho-zai Lene and dimethylformamide may be used alone or in combination of two or more thereof.

In the step S1, the polymer ink may be prepared by calculating in advance the amount of ink, the number of drops of ink, and the concentration of the drug and the biocompatible polymer required for inkjet printing the drug carrier to be prepared.

The polymer ink may be prepared by adjusting the viscosity, surface tension and contact angle to form a drug carrier in a predetermined form.

Inkjet printing may be performed by a computer programmed to inkjet print an image file in the form of a drug carrier to be prepared in step S3.

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

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

The method may further include preparing the substrate by O ₂ plasma surface treatment before forming the drug carrier by the inkjet printing method in step S3.

The polymer drug carrier of the present invention for achieving the above object is formed by inkjet printing a polymer ink prepared by mixing a biocompatible polymer, a drug and an organic solvent.

The biocompatible polymer is polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid-glycolic acid copolymer, polyglycolic acid, Polytrimethylene carbonate, polybetahydroxybutyl acid, polysuccinimide, polyamino acid-derived polymer, poly-L-glatamic acid, poly-L-leucine, poly-L-lysine, polysaccharide, amylose, hydroxyethyl starch, Dextran, alginic acid, chitin, polyester, poly (β-hydroxyalkanoate), poly (α-hydroxy acid), polyglycolide, polylactide, poly (α-malic acid), poly (ω-hydr Hydroxy acid), poly-ε-caprolactone, poly (β-hydroxyalkanoate), poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4-diox Span-7-membered), poly (ester-carbonate), poly (glycolide-1,3-dioxane-2-membered), polyanhydr Ride, poly (seba anhydride), polyorthoester, polycarbonate, poly (1,3-dioxane-2-membered), poly (amide ester), polydepsipeptide, poly (α-cyano Acrylates), poly (ethyl-α-cyanoacrylates), and polyvinyl alcohols, alone or in combination thereof.

The organic solvent is tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethyl sulfoxide, butanol, isopropanol, isobutyl alcohol, tetra butyl alcohol, acetic acid, 1,4-dioxane, toluene, ortho-xylene And dimethylformamide may be used alone or in combination of two or more thereof.

The polymer ink may be prepared by adjusting the amount of ink, the number of drops of ink, and the concentration of the drug and the biocompatible polymer according to the drug carrier to be prepared.

The polymer ink may be prepared by adjusting the viscosity, surface tension and contact angle to form a drug carrier in a predetermined form.

The polymer drug carrier can be controlled by the amount of ink, the number of droplets of ink and the concentration of the drug and the biocompatible polymer is made of a polymer ink is controlled to control the drug release amount, release rate.

The present invention provides a drug carrier that can be produced in various three-dimensional forms by an inkjet printing method using a polymer ink prepared to control drug release, and when using it, the drug release can be customized according to the patient. Not only can the drug delivery be precisely controlled, but the efficiency of drug administration can be increased to alleviate the pain of the patient.

In addition, the present invention provides a method for producing a polymer drug carrier using an inkjet printing method, it is possible to manufacture a variety of three-dimensional drug carriers to be uniform in shape and size, the process is simple, low defect rate, high reproducible molecules Drug carriers can be prepared. In addition, since the process of the present invention is carried out at room temperature, it does not impair the biological activity of the biocompatible polymer included in the polymer ink, and a drug carrier can be prepared using a small amount of ink and drugs.

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

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

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

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

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 ε-caprolactone (PCL), polylactic acid (PLA); Poly-L-lactide (PLLA), poly-D, L-lactide (PDLLA), poly (glycolic acid; PGA), poly Lactide-co-caprolactone (PLCL), polylactic-co-glycolic acid (PLGA), polyglycolic acid (PG), poly Polytrimethylenecarbonate (PTMC), polybeta-hydroxybutyrate (PHB), polysuccinimide (PSI), polyamino acid-derived polymer, poly- L-Glutamic Acid, Poly-L-leucine, Poly-L-lysine, Polysacchrides, Amylose, Hyde Hydroxyethyl starch, dextran, alginic acids, chitin, polyesters, poly (β-hydroxyalkanoate), poly (α-hydroxy acid) (pol y (α-hydroxy acids)); Polyglycolide, polylactide, poly (α-malic acids), poly (ω-hydroxy acids), poly- ε-caprolactone, poly (β-hydroxyalkanoate), poly (ester-ether), poly (1, 4-dioxane-2-one) (poly (1,4-dioxane-2-one)), poly (1,4-dioxane-7-one) (poly (1,4-dioxpan-7-one) ), Poly (ester-carbonate), poly (glycolide-1,3-dioxane-2-one) (poly (glycolide-1,3-dioxane-2-one) ), Polyanhydride, poly (sebacic anhydride), polyorthoester, polycarbonate, poly (1,3-dioxane-2- (Poly (1,3-dioxane-2-one)), poly (amide ester), polydepsipeptide, poly (α-cyanoacrylate) (poly (α-cyanoacryl ate)), poly (ethyl-α-cyanoacrylate), polyvinyl alcohol, or the like, may be used alone or in copolymerization.

In the present invention, the drug included in the polymer ink is not limited, and any solid drug or liquid drug may be used.

As the organic solvent capable of preparing the polymer ink by dissolving the above-described biocompatible polymer and drug, any one can be used as long as it can produce the polymer ink by dissolving it according to the type of biocompatible polymer and drug used. For example, tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethyl sulfoxide, butanol, isopropanol, isobutyl alcohol, tetra butyl alcohol, acetic acid, 1,4-dioxane, toluene, ortho-xylene , Dimethylformamide may be used alone or in combination, but is not necessarily limited thereto.

In the process of preparing the polymer ink, it is important to calculate the amount of ink, the number of drops of ink, and the concentration of the drug and the biocompatible polymer in advance for inkjet printing the drug carrier to be prepared.

Using the inkjet printing method, the amount of ink required to prepare one drug carrier, the number of drops of ink, and the concentration of the drug and the biocompatible polymer are prepared in advance to prepare the polymer ink, thereby determining the rate of drug release and the amount of drug administered. I can regulate it.

In addition, in order to match the sprayable properties of the polymer ink so that the drug carrier can be formed in the desired form, the polymer ink is prepared by adjusting the viscosity, surface tension, and contact angle between the substrate and the ink.

More specifically, the viscosity of the polymer ink can be adjusted according to the amount of the polymer. In the case of a polymer, it is necessary to adjust it because the viscosity tends to increase rapidly. Most of the polymers have different amounts (concentrations) because they match the characteristics of the ink, but the range of viscosity is relatively similar. Surface tension can be controlled by varying the composition of the solvent. The solvent having a high surface tension and a low solvent can be appropriately mixed and adjusted. Since the contact angle is a natural value of the substrate and the ink, the resolution can be adjusted when printing through the contact angle without separately adjusting the contact angle. Adjusting the resolution is equivalent to setting the position where the next ink drops after one ink drop is dropped. As described above, the desired pattern can be accurately obtained by setting the viscosity, surface tension, and contact angle of the polymer ink well.

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

Since the process of injecting the polymer ink prepared according to the above-described method into the inkjet printer cartridge and then mounting the printer to the printer may be easily performed by one of ordinary skill in the art, a detailed description thereof will be omitted. .

As the printer that can be used in the present invention, an inkjet printer can be used, and is not particularly limited.

Finally, a computer programmed to produce a drug carrier of the desired shape is connected with the inkjet printer and then inkjet printed onto the substrate to form the drug carrier (step S3).

Substrates that can be used in the present invention may be a plate or film made of a polymer such as slide glass, paper, silicon wafer, polyimide (PI), polyethylene terephthalate (PET), polystyrene (PS), or the like. It may be used without limitation as long as it can print a polymer ink.

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

In step S3, an image file (eg, a bitmap image file) in the form of a drug carrier is connected to an inkjet printer and a computer programmed to be inkjet printed as it is and inkjet printed on the substrate is laminated to form a three-dimensional shape. Drug carriers can be prepared.

In the present invention, the drug carrier is a circle, a grid, a honeycomb, a ring, a rod, a square, a star, and a triangle. It can be manufactured in a three-dimensional form, such as, without being limited to this can be manufactured in a variety of forms, of course.

According to the present invention, when manufacturing a three-dimensional drug carrier in a lamination method by precisely calculating and inkjet printing by a computer program, the shape, size, height, and the like can be uniformly manufactured, and a computer program can be used on one substrate. Several forms of drug delivery can be printed at one time (see FIG. 2).

Since the process of forming the drug carrier by inkjet printing and laminating the polymer ink in step S3 is performed at room temperature, the drug carrier can be prepared without impairing the biological activity of the biocompatible polymer.

In addition, the present invention provides a polymer drug delivery body formed by inkjet printing a polymer ink prepared by mixing a biocompatible polymer, a drug and an organic solvent, and can be prepared 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.

Polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA), and a fluorescent dye were dissolved in dimethylacetamide (DMAc) to prepare a polymer ink, and the temperature of the solution was raised to 40 to 50 ° C. A fluorescent ink was used in place of the drug to prepare a polymer ink.

When dissolution was completed, the viscosity and the surface tension of the polymer ink was measured to determine whether it was within an appropriate range. The appropriate range was dependent on the experimental values because the characteristics of the polymer inks differed. The range of viscosities and surface tensions suitable for use in the printing system constructed in this experiment ranged from 3 to 20 cps with surface tensions of over 20 dynes / cm for inks made of fluorescent dyes and polymers.

Subsequently, drug carriers are placed in a circle, grid, honeycomb, ring, rod, square, star, and triangle. A bitmap image to be printed was created and the surface area of each image and the amount of ink required were calculated as shown in Table 1 below. Before printing drug carriers having different concentrations of fluorescent dyes and stacking numbers, the amount of polymer ink and fluorescent dyes to be used for each drug carrier was calculated and shown in Table 2.

Using the method of manufacturing a polymer drug carrier using the inkjet printing method of the present invention, it is possible to manufacture a drug carrier using a small amount of polymer ink and drugs, there is an advantage that can accurately calculate the amount of material to be used in advance. By using the polymer ink prepared in this way by inkjet printing on a slide glass to prepare a drug carrier of various forms as shown in FIG.

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

By using the polymer ink prepared as described above, the number of stacked layers was 30, and inkjet printing was performed on the slide glass in the same manner as in Example 1 to prepare various types of drug carriers.

Fluorescence images of the drug carrier prepared according to Example 2 are shown in FIG. 4.

As can be seen in Figure 4, by printing the prepared ink in an inkjet printer it was possible to uniformly prepare a polymer drug carrier of a complex pattern.

Test Example  One: Example  Three-dimensional structural analysis of drug carriers prepared according to

Different types of drug carriers prepared according to Example 1 were photographed with nanoviews to analyze three-dimensional structures, and the results are shown in FIGS. 5A and 5B.

Referring to FIG. 4, the diameters of the different types of drug carriers were measured as 330-750 μm and the height was about 6 μm, and the heights of the simple drug carriers such as round, ring, square, triangle, and rod are high. It showed a tendency to appear, but the bitmap image and the error were printed less.

Test Example  2: bitmap image In the example  Size Comparison of Prepared Drug Carriers

The drug carriers of the round, lattice, honeycomb, ring, rod, rectangle, star, and triangle prepared in the above examples and the bitmap images used to prepare the same are shown in Table 3 below.

Referring to Table 3, according to the present invention, the different types of drug carriers inkjet printed using the bitmap image were printed with a length of about 100% to about 106% of the length of the bitmap image. It can be seen that similarly printed. From this, when the polymer drug carrier is manufactured using the inkjet printing method according to the present invention, it can be seen that the drug carrier can be manufactured by printing in a desired form without material loss or complicated process.

Test Example  3: Example  Drugs prepared according to 1 Between carriers  Height, surface area and volume measurements

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

Referring to Table 4, the drug carriers prepared in Examples were found to have a large upper surface area in the order of honeycomb, lattice, ring, rectangle, star, rod, circle, and triangle, but the volume between them It can be seen that the difference is not as large as the surface area difference.

Test Example  4: Drug Release Rate Analysis of Drug Carriers

Fluorescent dye release rate was measured for each of the drug carriers of round, lattice, honeycomb, cyclic, rod, square, star, and triangle prepared in Example 1, and is shown in (a) and (b) of FIG. Indicated. In this embodiment, since the fluorescent dye was used instead of the drug, the fluorescent dye release rate means the actual drug release rate. Figure 6 (a) is a graph measuring the fluorescent dye release rate for the drug carriers prepared under the condition that the concentration of the fluorescent dye in the Example 3 mg / mL and the number of stacking 10, Figure 6 (b) is In the Examples, the concentration of the fluorescent dye was 10 mg / mL and the graph was measured for the fluorescent dye release rate for the drug carriers prepared under the condition of the number of stacked 20. Fluorescent dye release rate was calculated by immersing the drug carriers in a phosphate buffer solution, confirming the release and degradation for a total of 25 days, and summarized the results of the 80-minute release measurements.

Referring to (a) and (b) of Figure 6, it can be seen that the release rate of the fluorescent dye in the order of honeycomb, ring, lattice, star, square, rod, triangle, circular drug delivery in the order of fast. . It can be seen that the order of release rates in FIGS. 6 (a) and 5 (b) is similar, so that a specific mechanism is involved in the release rate, and that the order of rapid release rate and the large order of surface area are very similar. have. In addition, although the total volume of the drug carrier and the amount of dyeing agent are similar, it can be seen that the release rate is different according to the form of the drug carrier, and the part contacting the phosphate buffer solution such as the honeycomb, cyclic, and lattice drug carriers. It can be seen that the more structures, the faster the release rate. Taken together, these results suggest that the rate of drug release can be controlled by controlling the shape of the drug carrier.

In addition, the cyclic drug carrier prepared according to Example 1 was immersed in PBS (Phosphate Buffered Saline, Phosphate buffer solution) for 25 days to observe the process of hydrolysis. In this process, 14 days after the immersion in the cyclic drug carrier, phosphate buffer solution before being immersed in PBS and 25 days after immersion in the drug carrier and phosphate buffer solution by taking a scanning electron microscope picture of the drug carrier, respectively (a) of FIG. , (b) and (c).

According to Figure 7, after immersing the cyclic drug carrier in the phosphate buffer solution it was observed that the pores on the surface from 14 days, the pores on the surface was large and falling off on day 25.

Test Example  5: Example  Determination of drug release constant of drug carriers prepared according to 1

The drug carriers prepared in Example 1 use the Higuchi model of the following equation for the release rate constants of the drug carriers in honeycomb, lattice, ring, star, rectangle, rod, circle, and triangle. It was measured and shown in FIG.

[Equation]

Q = Kt ^1/2

In the above equation, Q is the partial drug release amount, 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 show linearity, which conforms to the Higuchi model. As such, the linear increase in cumulative release with respect to the square root of time in FIG. 7 means that the drug release from the drug carrier of the present invention is a controlled release.

Example 3 relates to a method for preparing a drug delivery vehicle containing the actual drug, namely paclitaxel (PTX), an anticancer agent.

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

Thereafter, bitmap images for printing the drug carriers in circles, grids, honeycombs, and rings were made and thus printed on the slide glass. At this time, the printing conditions were firing voltage (firing voltage) 20 ~ 23V, frequency 5 kHz, the temperature of the printer nozzle and plate was maintained at 28 ~ 31 ℃. In addition, the number of laminated layers was set to 30 to prepare a polymer drug carrier.

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 Plaid 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 Annular 0.34 6.5 25 3,477,864 367,405 1.56

The printed polymeric drug carrier was morphologically measured with a Nano view, High accuracy non-contact surface profiler.

According to Table 5, depending on the type of drug carrier, the amount of PTX loading and the weight of the carrier were the same or similar. In addition, the volume of drug carrier was large or small in the range of about 10%.

In contrast, the total surface area of the drug carrier showed a big difference by shape, and the surface area was broad in the order of honeycomb>lattice>ring> circle. In particular, the honeycomb type, which has many holes and complex shape, has a surface area of about 2.46 times larger than that of the circular shape, and the surface area of lattice pattern and annular shape that is about 1.56 ~ 1.69 times larger than that of the circular shape.

Test Example  6: Example  Drug release rate by type of polymer drug carrier prepared according to 3

5 mL of PBS (pH 7.4) containing 0.1% of 200 drug carriers of the same type and an emulsifier of Polyoxyethyelene Sorbitan Monooleate (trade name tween 80) was 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 ℃ water. After taking the sample, a new sample of 5 mL of PBS containing 0.1% of tween 80 was replaced and the next sample was taken.

PTX drug release rate analysis was performed using high-performance liquid chromatography (HPLC) and UV detector, where UV wavelength was 205 nm, flow rate 1.0 mL / min, and mobile phase was 50:50 ratio of AcN and water. It was used by mixing.

Drug release rate graphs according to Test Example 6 are shown in FIGS. 9A and 9B. Here, FIG. 9A shows the cumulative daily discharge amount, and FIG. 9B shows the initial burst for the first 0-6 hours in the graph of FIG. 9A.

9A and 9B, on the first day, an initial burst occurred due to PTX release on the outer surface of the drug carrier, and PTX was gradually released from day 2.

By the type of drug carrier, honeycomb releases nearly 100% PTX on day 6, 80% lattice and annular, and 60% round. It was found that the larger the surface area, the larger the contact area with PBS, and the faster the release rate.

10 is a SEM image showing the decomposition of the drug carrier prepared according to Example 3 with time.

According to FIG. 10, in 'Day 0', the drug carrier before the dissolution test may be printed on the substrate. On day 2, the hydrolysis reaction occurred in PBS, and the degradation of drug carriers was observed. In particular, it was observed that the pattern disappeared almost in the lattice pattern.

On day 4, morphological distortion of the drug carriers occurred and degradation occurred. Then, on day 6, the morphology changed and the decomposition proceeded more so that the original morphology was not recognizable. At this time, in the lattice, honeycomb, and cyclic drug carriers except for the round, it was sometimes broken. As in the degradation rate graph, it was confirmed that the degradation of the circular drug carrier was the slowest in the form.

Test Example  7: Example  Determination of drug release constant of drug carriers prepared according to 3

The drug carriers prepared in Example 3 measured the release rate constants of the drug carriers of circular, lattice, honeycomb, and ring using the Hikuchi model of the equation given in Test Example 5. The results are shown in FIG.

According to FIG. 11, the graphs of different forms of drug carriers show linearity, conforming to the Higuchi model, which means that drug release from drug carriers prepared according to Example 3 of the present invention is controlled release. do.

Test Example  8: Example  In vitro of drug carriers prepared according to In in vitro Cytotoxicity test

Cell cytotoxicity was measured for 48 hours by WST assay.

Into a well of a 24 well plate (24 well plate) was added DMEM, HeLa cells containing 10% FBS and 1% P / S by 1 x 10 ⁴ , and cultured the cells in a cell incubator for 24 hours. After culturing, the number of drug carriers prepared according to Example 3 was varied, that is, the cells were put in different concentrations and cultured for a predetermined time.

After reaching a certain time, the WST reagent was added to the well, and incubated in the cell incubator for 1 hour. 100 μL of the supernatant was collected into a well of a 96-well plate and OD at 440 nm using a micro spectrophotometer. Optical Density) value was measured.

A graph of the relationship between drug concentration and cell viability according to Test Example 8 is shown in FIG. 12.

According to Figure 12, the more the number of drug carriers put, that is, the higher the drug concentration, the higher the cytotoxicity was confirmed that the cell viability is reduced.

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

These results indicate that PTX is continually released from the drug carrier and its release affects cytotoxicity, ie, cell viability.

Claims (15)

Preparing a polymer ink by mixing a biocompatible polymer, a drug and an organic solvent (S1);
Injecting the polymer ink into a printer cartridge and mounting the ink to a inkjet printer (S2); And
Connecting a computer programmed to produce a drug carrier of a desired shape with the inkjet printer and then inkjet printing a polymer ink onto a substrate to form a drug carrier (S3);
Method for producing a polymer drug carrier using an inkjet printing method comprising a.
The method according to claim 1,
The biocompatible polymer is polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid-glycolic acid copolymer, polyglycolic acid, Polytrimethylene carbonate, polybetahydroxybutyl acid, polysuccinimide, polyamino acid-derived polymer, poly-L-glatamic acid, poly-L-leucine, poly-L-lysine, polysaccharide, amylose, hydroxyethyl starch, Dextran, alginic acid, chitin, polyester, poly (β-hydroxyalkanoate), poly (α-hydroxy acid), polyglycolide, polylactide, poly (α-malic acid), poly (ω-hydr Hydroxy acid), poly-ε-caprolactone, poly (β-hydroxyalkanoate), poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4-diox Span-7-membered), poly (ester-carbonate), poly (glycolide-1,3-dioxane-2-membered), polyanhydr Ride, poly (seba anhydride), polyorthoester, polycarbonate, poly (1,3-dioxane-2-membered), poly (amide ester), polydepsipeptide, poly (α-cyano Acrylate), poly (ethyl-α-cyanoacrylate) and polyvinyl alcohol alone or a copolymer thereof, a method for producing a polymer drug carrier using an inkjet printing method.
The method according to claim 1,
The organic solvent is tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethyl sulfoxide, butanol, isopropanol, isobutyl alcohol, tetra butyl alcohol, acetic acid, 1,4-dioxane, toluene, ortho-xylene And dimethylformamide. The method for preparing a polymer drug carrier using an inkjet printing method, characterized in that one or more selected from the group consisting of dimethylformamide.
The method according to claim 1,
The polymer ink in the step S1 is prepared by calculating in advance the amount of ink, the number of drops of ink and the concentration of the drug and the biocompatible polymer required for inkjet printing the drug carrier to be prepared, the polymer drug using the inkjet printing method Method of manufacturing the carrier.
The method of claim 4,
The polymer ink is a method of manufacturing a polymer drug carrier using an inkjet printing method, characterized in that the prepared by adjusting the viscosity, surface tension and contact angle to form a drug carrier in a predetermined form.
The method according to claim 1,
Inkjet printing is performed by a computer programmed to print the image file in the form of a drug carrier to be prepared in step S3 by inkjet printing method of the polymer drug carrier using the inkjet printing method.
The method according to claim 1,
In the step S3, the drug carrier is a polymer drug carrier using the inkjet printing method, characterized in that formed by printing a polymer ink on a substrate and laminated in three-dimensional form.
The method according to claim 7,
The three-dimensional shape is a method of producing a polymer drug carrier using an inkjet printing method, characterized in that the three-dimensional shape selected from the group consisting of circular, lattice pattern, honeycomb, ring, rod, square, star and triangle.
The method according to claim 1,
The method of preparing a polymer drug carrier using the inkjet printing method further comprises the step of preparing the substrate by O ₂ plasma surface treatment before forming the drug carrier by the inkjet printing method in step S3.
A polymer drug carrier formed by inkjet printing a polymer ink prepared by mixing a biocompatible polymer, a drug and an organic solvent.
The method according to claim 10,
The biocompatible polymer is polycaprolactone, polylactic acid, poly-L-lactide, poly-D, L-lactide, polyglycolic acid, polylactide caprolactone, polylactic acid-glycolic acid copolymer, polyglycolic acid, Polytrimethylene carbonate, polybetahydroxybutyl acid, polysuccinimide, polyamino acid-derived polymer, poly-L-glatamic acid, poly-L-leucine, poly-L-lysine, polysaccharide, amylose, hydroxyethyl starch, Dextran, alginic acid, chitin, polyester, poly (β-hydroxyalkanoate), poly (α-hydroxy acid), polyglycolide, polylactide, poly (α-malic acid), poly (ω-hydr Hydroxy acid), poly-ε-caprolactone, poly (β-hydroxyalkanoate), poly (ester-ether), poly (1,4-dioxane-2-one), poly (1,4-diox Span-7-membered), poly (ester-carbonate), poly (glycolide-1,3-dioxane-2-membered), polyanhydr Ride, poly (seba anhydride), polyorthoester, polycarbonate, poly (1,3-dioxane-2-membered), poly (amide ester), polydepsipeptide, poly (α-cyano Acrylate), poly (ethyl-α-cyanoacrylate) and polyvinyl alcohol alone or a copolymer thereof.
The method according to claim 10,
The organic solvent is tetrahydrofuran, dimethylacetamide, dimethylformamide, chloroform, dimethyl sulfoxide, butanol, isopropanol, isobutyl alcohol, tetra butyl alcohol, acetic acid, 1,4-dioxane, toluene, ortho-xylene And dimethylformamide, wherein the polymer drug carrier is one or a mixture of two or more selected from the group consisting of dimethylformamide.
The method according to claim 10,
The polymer ink is a polymer drug carrier, characterized in that produced by adjusting the amount of ink, the number of drops of ink and the concentration of the drug and biocompatible polymer according to the drug carrier to be prepared.
The method according to claim 13,
The polymer ink is a polymer drug carrier, characterized in that prepared by adjusting the viscosity, surface tension and contact angle to form a drug carrier in a predetermined form.
The method according to claim 10,
The polymer drug carrier is a polymer drug carrier, characterized in that the amount of ink, the number of drops of ink and the concentration of the drug and the biocompatible polymer is made of a polymer ink is controlled to control the drug release amount, release rate.

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