KR101171888B1 - Method for manufacturing micro-needle comprising drug-containing nano particle and micro-needle manufactured using the same - Google Patents

Abstract

The present invention comprises a first step of forming a micro needle by applying a solution containing drug-containing nanoparticles to a mold formed with a micro needle pattern; And a second step of melting and removing the mold from the microneedles formed in the first step, wherein the mold has a melting point at room temperature or higher, and a method of manufacturing a microneedles and the microneedles manufactured thereby. It is about. According to the manufacturing method of the microneedle according to the present invention, by using the drug-containing nanoparticles to improve the absorption of the drug and to facilitate the increase of the content of the drug, it provides a microneedle of excellent hardness and strength and maintain a sharp shape can do.

Description

Method for manufacturing micro-needle comprising drug-containing nanoparticles and a micro-needle manufactured thereby Method of manufacturing micro-needle comprising drug-containing nano particle and micro-needle manufactured using the same

The present invention relates to a method for producing a microneedle comprising drug-containing nanoparticles and to a microneedle produced thereby.

The drug delivery system is designed to control the release and absorption of the drug or to target and deliver the drug to a specific part of the body, and to reduce the side effects of the drug and maximize the efficacy to effectively maintain the required amount of drug at the target site for a certain time. It is intended to be adjusted.

Among these, transdermal drug delivery is a method of drug delivery systemically through various stratum corneum layers of the skin, and has many advantages. In other words, when using transdermal drug delivery, the gastrointestinal degradation and liver metabolism can be avoided, and when side effects occur, users can remove it very easily, and the drug release type can be easily controlled. There is this.

On the other hand, the stratum corneum, the outermost layer of skin, is the major cause of drug transfusion in transdermal drug delivery, and transdermal permeation using passive diffusion through the skin has a low molecular weight of 500 g / mol or less, high lipid affinity, There was a limitation to have one required dose.

Conventional formulations such as ointments, creams, lotions, popping agents, adhesives and the like have been used for the purpose of topical administration to the skin disease site by passive transdermal drug delivery technology, but recently to enhance skin permeability, which is a problem of these formulations. Active transdermal drug delivery technology is attracting attention.

The active transdermal drug delivery technique is a useful technique that allows the correct drug to arrive at the right place at the right time. Devices used for such drug delivery are finely sized to store and use drugs smaller than μl, and examples of such drug delivery devices include micro / nano needles, micro / nano pumps, micro / nano valves and implantable drugs. Transfer elements and the like can be used.

In particular, the microneedle, which has a length of several hundred microns, enables local painless delivery of drugs to cells or tissues, and is difficult to administer or treat molecules that cannot penetrate biological membranes such as peptides, proteins, oligonucleotides, and DNA. And target delivery of drugs to specific parts or tissues of the body.

Conventionally, such microneedles were manufactured by using micromachining or MEMS in the same metal or silicon material as the injection needle. However, around 2000, a method of manufacturing microneedles using various types of biomaterials has been developed to improve percutaneous permeation efficiency. Recently, microneedles having body fluid collection, drug delivery, or all of the above functions have been devised. .

However, in the related art, since the microneedle was manufactured using a solid micro mold, it was difficult to detach the mold and the needle while maintaining the microneedle shape, so that the microneedle tip was difficult to maintain the sharpness. Since it is located in the tip in the form or solution, it is difficult to control the physical properties of the microneedle tip, there is a problem that it is difficult to control the skin permeation characteristics.

The present invention was created to solve the above-mentioned problems of the prior art, an object of the present invention is to produce a mold having a microneedle pattern using a heat-melt material having a melting point of room temperature or more, and drug-containing nano using the mold The manufacture of microneedles containing particles provides microneedles and methods for their preparation that not only have brittleness and modulus suitable for skin penetration due to their excellent hardness and strength, but also maintain a sharp shape.

The present invention provides a means for solving the above problems, the first step of forming a microneedle by applying a solution containing the drug-containing nanoparticles to a mold formed with a microneedle pattern; And a second step of melting and removing the mold from the microneedle formed in the first step, wherein the mold has a melting point at room temperature or higher.

The present invention as another means for solving the above problems, the present invention provides a microneedle containing 10 to 90 parts by weight of the drug-containing nanoparticles.

According to the present invention, since the microneedle is formed by using a mold including a heat-melt material having a melting point of room temperature or higher, the sharpness of the microneedle tip may be maintained while the mold and the needle are separated, and the drug may be contained. Since the microneedle is manufactured using nanoparticles, the absorbency of the drug is improved and the content of the drug is easily increased, and there is no need to use various organic solvents or use extreme pH.

In addition, the microneedles thus prepared may have excellent brittleness and modulus that are excellent in hardness and strength and effective in penetrating the skin.

1 is a process diagram schematically showing a method of manufacturing a microneedle according to an embodiment of the present invention,
2 is an electron micrograph showing a microneedle according to Example 1 of the present invention.
Figure 3 shows the compressive strength test results of the microneedle according to Examples 1, 3 and 6 of the present invention.

The present invention comprises a first step of forming a micro needle by applying a solution containing drug-containing nanoparticles to a mold formed with a micro needle pattern; And a second step of melting and removing the mold from the microneedle formed in the first step, wherein the mold includes a heat-melt material having a melting point of room temperature or more.

Hereinafter, a method of manufacturing the microneedle according to the present invention will be described in detail.

Microneedle manufacturing method according to the present invention, as described above, the first step of forming a microneedle by applying a solution containing drug-containing nanoparticles to a mold formed with a microneedle pattern; And a second step of melting and removing the mold from the microneedle formed in the first step.

Here, the first step is a step of molding the microneedle containing the drug-containing nanoparticles using a mold having a microneedle pattern.

The mold used in the present invention includes a heat-melt material having a melting point of room temperature or more. Since the melting point is room temperature or more, a mold having a predetermined shape as a solid state at room temperature can be formed and can be easily melted by heating. After molding the microneedles using a mold, only the mold can be easily removed without damaging the shape of the microneedles.

The method of manufacturing the mold is not particularly limited as long as it is a method for manufacturing a mold including a heat melting material having a microneedle pattern formed on one surface and a melting point of which is higher than or equal to room temperature. After melting in a sol state and put in a cylindrical container, the microneedle-shaped disk to be manufactured is injected onto the heat-melt material, and then cooled by one side of the disk according to the microneedle shape of the disk. A mold in which a microneedle pattern is formed may be manufactured.

As used in the present invention, the "heat-melt material", as described above, is a room temperature or more, and exists as a solid at room temperature, and includes all materials that can be melted by applying heat.

Although the type and melting point of the heat-melt material are not particularly limited, for example, a material such as a solvent or a polymer having a melting point of 20 to 60 ° C. may be used.

If the melting point of the heat-melt material is less than 20 ℃, since it exists in a liquid state at room temperature, there is a fear that a separate cooling treatment process for maintaining the heat-melt material in a solid state when forming the microneedles, When the temperature exceeds 60 ° C., degeneration of the drug or protein to be molded may occur or the microneedles as well as the mold may be melted together depending on the heating temperature, and thus it may be difficult to prepare microneedles having a sharp shape.

In addition, the kind of the heat-melt material is not particularly limited, but for example, polyalkylene glycol, alkyl stearate or polydialkylsiloxane, etc. may be included alone or two or more, specifically, polyalkylene Glycols, C ₁ to C ₁₂ alkyl stearates and polydialkylsiloxanes, etc. may be included alone or two or more, more specifically polyethylene glycol, C ₁ to C ₈ alkyl stearate, polydimethylsiloxane and poly It may include diethylsiloxane alone or two or more, more specifically, may include ethyl stearate.

On the other hand, the "drug-containing nanoparticles" refers to the nano-sized crystal particles containing the drug. Here, the drug is contained in the microneedle and can be used for skin permeation, and may include all drugs known in the art, and the kind thereof is not particularly limited, but for example, a low molecular weight drug having a molecular weight of 500 or less As a drug, such as naproxen, ibuprofen, aspirin, gleevec, paclitaxol, and the like, the drug may be prepared by chemical synthesis or obtained by extraction from plants, as well as protein drugs such as proteins, peptides, nucleic acid therapeutic agents and the like having a high molecular weight.

On the other hand, the method for preparing the drug-containing nanoparticles may include a variety of methods known in the art, and is not particularly limited, for example, thermodynamic methods or mechanical energy or electrical energy depending on the polymer material, etc. Dynamic methods using high energy may be used, and the thermodynamic method and the dynamic method may be used in combination.

Specifically, drug-containing nanoparticles can be prepared using dynamic methods that are effective for overcoming surface energy, and more specifically, drug-containing nanoparticles can be prepared by grinding using mechanical energy.

The drug-containing nanoparticles can be prepared by grinding to a nano size through a variety of milling methods known in the art, such as, for example, ball milling method, fluid energy milling method, media milling method and high pressure homogenization method It may be carried out using any one method selected from the group consisting of, and more specifically, it can be carried out through the ball milling method in that the aggregation of particles can be prevented.

As a specific example of the ball milling method, it may be carried out using a cylindrical vessel having a grinding media and a port for loading and discharging the drug material, wherein the cylindrical vessel has a shaft Particle size can be greatly reduced by a cascading action that rotates and causes the abrasive medium to hit the wall and fall off.

Here, the critical speed is the speed at which the polishing medium stops the cascading action due to the centrifugal force during the rotation, and may rotate slower than the critical speed so that the cascading action can be maintained. In this case, the friction has a greater influence on the reduction in particle size as the rotational speed decreases.

The polishing medium may use those conventionally used in the art in consideration of shape, density, size, and hardness, and when the polishing medium having a high density and hardness is used, the particle size may be reduced more quickly. .

Although the shape and type of the polishing medium used for the grinding is not particularly limited, for example, a solid matrix may be used, and the solid matrix may be spherical, cylindrical, rod, wire, plate or foil or the like. It may be used in various forms, the size is not particularly limited.

For example, the polishing medium may be made of metal, metal oxide, polymer, glass, semiconductor material or ceramic material, and more specifically, zirconia beads, yttria-stabilized zirconia beads, glass beads and polystyrene beads. It may include one or more selected from the group consisting of.

On the other hand, the size of the drug-containing nanoparticles used in the present invention is not particularly limited, for example, may have a particle diameter of 50 to 1000nm.

As described above, the drug-containing nanoparticles used in the present invention have an advantage of easy loading, and thus, mechanical properties such as hardness improvement of the needle are enhanced, so that the needle can be easily separated after skin permeation and skin permeation.

In addition, the method of molding the mold having the microneedle pattern of the first step is not particularly limited, but, for example, injecting and cooling a microneedle-shaped disk into a separation vessel containing a heat-melt material in a molten state. (One); And (2) separating the disc from the heat-melt material cooled in step (1).

That is, as in step (1), by injecting the microneedle-shaped disc on the hot-melt material contained in a molten state in a separate shape of a predetermined shape and then cooling the hot melt material to the micro-needle-shaped disc It can be shaped to have a corresponding intaglio microneedle pattern.

In addition, the microneedle shape may be appropriately employed depending on the shape and size of the microneedle to be manufactured in the present invention, and is not particularly limited.

The cooling condition is not particularly limited, but may be, for example, quenching at a temperature of −15 to −20 ° C. for 1 to 4 hours.

In the step (1), when the heat-melt material in the molten state is cooled in a state in which a microneedle pattern is formed on one surface by a microneedle-shaped disc, as in step (2), it is cooled in the step (1). A mold having a microneedle pattern can be formed by separating the disc from the hot melt material. The mold thus obtained may have a microneedle pattern on one surface as described above.

In addition, in the first step, the microneedles may be formed by applying a solution containing drug-containing nanoparticles onto a mold, followed by centrifugation or precipitation.

Here, the temperature and the rotational speed during the centrifugation are not particularly limited, but may be centrifuged at a speed of 1000 to 8000 rpm at a temperature of 0 to 10 ° C., and the vacuum or oven is dried after forming the microneedle shape. You can.

Accordingly, the microneedle including the drug-containing nanoparticles can be formed.

Subsequently, the second step is melting and removing the mold in order to separate and remove the mold from the microneedle formed in the first step.

The mold may be easily melted by heat treatment, and as in the conventional method of manufacturing a microneedle using a solid mold, the mold and the microneedle are not separated through a separate desorption process, but include a heat-melt material. Since it is to be separated and removed from the microneedle by melting of the mold itself, it is possible to prevent the sharpness (sharpness) of the needle tip that occurs during the detachment of the microneedle.

Herein, the melting of the second step may be appropriately performed within temperature and time conditions in which only the mold may be melted and separated from the microneedles, and the heat treatment conditions are not particularly limited. It may be carried out for 1 to 12 hours at a temperature of ℃.

If the heat treatment deviates from the temperature and time conditions, the excipients are not completely melted and the heat-melting material remains on the surface of the microneedles, or conversely, damages not only the surface of the microneedles but also drugs or proteins contained in the microneedles. There is a risk of making.

Hereinafter, referring to FIG. 1, a method of manufacturing a microneedle according to an embodiment of the present invention will be described. A needle having a microneedle shape in a support material 10 in a liquid state contained in a cylindrical container will be described. (30), and after freezing, the microneedle-shaped disc 30 is separated and the drug-containing nanoparticles 50 are included on a mold made of the solidified heat-melt material 10. Solution can be injected.

Subsequently, the drug-containing nanoparticles 50 may be centrifuged or precipitated, and then the heat-melt material 10 may be melted again by drying.

Accordingly, the microneedle 100 having the microneedle tip 110 as shown in FIG. 1 may be manufactured.

The invention also relates to microneedles comprising 10 to 90 parts by weight of drug containing nanoparticles.

The microneedle of the present invention maintains the sharpness of the microneedle tip and manufactures the microneedle using drug-containing nanoparticles, thereby improving the absorbency of the drug and increasing the content of the drug, and the use of various organic solvents. However, there is no need to use extreme pH.

Thus, conventional microneedles may typically contain about 10 parts by weight of a drug, while the present invention may include 10 to 90 parts by weight, more preferably about 40 to 70 parts by weight of drug containing nanoparticles.

The tip of the microneedles of the present invention may be any suitable size and shape within the size and shape ranges commonly used in the art, for example, a bottom surface having a diameter or one side length of 150 to 500 ㎛; And a cone having a height of 100 to 800 μm, a radius of the tip less than 30 μm.

In addition, the microneedle of the present invention may further include a pharmaceutically acceptable carrier in addition to the drug-containing nanoparticles, thereby improving hardness and strength, thereby having brittleness and modulus suitable for skin penetration.

Stabilizers can be used as the carrier. The stabilizer is added to impart various properties of drug delivery by varying the chemical and physical structure of the drug. For example, when the state of the nanoparticles is unstable when changing from a solid phase to a liquid phase, the stabilizer is stabilized. Can play a role.

The stabilizer is a substance that stabilizes the structure so that cracking or collapse does not occur due to volume change due to chemical reaction or crystal transition, and the type of the stabilizer is not particularly limited, but for example, hydroxy alkyl cellulose , Polyvinylpyrrolidone, chitosan, polyamino acid, lecithin, polyoxyethylene, poloxamer (pluronic), polypropylene glycol, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, sorbic acid, potassium sorbate, benzoic acid, benzoic acid Proteins including sodium, propylparaben, methylparaben, polyvinylalcohol, carrageic acid, alginic acid, sodium alginate, gluconic acid or phenylalanine, polyaniline, polypyrrole, cellulose acetate, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, phosph Porridge, sorbitan, fatty acid esters and potassium sorbate Can be used.

Specific examples include hydroxy alkyl cellulose, polyvinylpyrrolidone, pluronic, chitosan and polyamino acid, and the like, and more specifically hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP; polyvinylpyrrolidone), Pluronic (pluronic) F-127, Pluronic F-68, chitosan (chitosan) and polyamino acid may include one or more selected from the group consisting of copolymers.

In the case of the stabilizer, the kind of drug used together is not particularly limited, but, for example, when the drug is a chemical drug, a polymer stabilizer may be used together to stabilize the structure of the chemical drug. .

In addition, it is possible to use an excipient which is commonly added in the manufacture of a medicament to make the medicament easy to eat or to form a certain form with the carrier.

As the excipient, the kind is not particularly limited, but, for example, lactose, sorbitol, mannitol, sucrose, sugar, xylitol, and erythritol Trehalose, naproxen, lipoic acid, calcium phosphate, calcium silicate, citric acid, croscarmellose sodium, cyclodextrin, dextrose (dextrose), glucose (glucose), lactic acid (lactic acid), lactitol (lactitol), maltitol (maltitol), maltodextrin (maltodextrin), maltose, propionic acid, sodium chloride, Sodium phosphate, hydroxyalkyl cellulose, polyvinyl alcohol_, povidone, alkylene glycol, polyalkylene oxide, poloxame r), polydextrose, albumin, alginic acid, sodium alginate, sodium alginate, hydroxypropyl methylcellulose, cellulose, methyl cellulose Starch, crospovidone, pluronic, tyloxapol, plasdone, dextran, benzthonium chloride, benzalconium chloride chloride), acacia rubber, gelatin, microcrystalline cellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, phosphory The feed, sorbitan, fatty acid esters, potassium sorbate, magnesium stearate, mineral oil and the like may be included alone or two or more.

Excipients included in the microneedle according to the present invention, more specifically, may include one or more selected from the group consisting of lactose, sucrose, mannitol, sorbitol, xylitol, trehalose, naproxen and lipoic acid.

In addition, when the excipient is contained together with the protein drug, it is not particularly limited, but may have, for example, a nanoparticle form.

The carrier is not particularly limited in content so that the physical properties of the drug-containing nanoparticles can be improved, for example, may include 10 to 300 parts by weight of the carrier relative to 100 parts by weight of the drug. If the content is less than 10 parts by weight, the hardness and strength of the microneedle is lowered, it is difficult to easily pass through the stratum corneum, if the content exceeds 300 parts by weight, it is difficult to carry a high concentration of the drug In addition, low drug concentrations may reduce the rate of drug delivery in the skin.

In addition, the material to be mixed to improve the physical properties of the microneedle, it may further include a physical property improving agent for improving mechanical properties such as hardness and strength to maintain the shape of the microneedle.

The physical property improving agent is not particularly limited in kind, but may include, for example, at least one selected from the group consisting of polylactic acid, polylactic acid-co-polyglycolic acid, polyethylene glycol-polyester, and polyamide. Can be.

As mentioned above, the present invention can exhibit microneedles excellent brittleness and modulus properties. This may be affected by the type and content of the drug-containing nanoparticles and the carrier.

According to one embodiment of the present invention, the modulus may be lowered as the content of the drug-containing nanoparticles increases.

According to another embodiment of the present invention, lactose as compared to hydroxy propyl cellulose may provide a greater effect on achieving good mechanical strength.

From the above, the modulus value of the microneedles of the present invention by adding drug-containing nanoparticles and / or carriers may be between 0.1 and 500 MPa.

Hereinafter, the present invention will be described in more detail with reference to the following examples and comparative examples, but the scope of the present invention is not limited by the following examples.

Preparation Example 1 Preparation of Drug-Containing Nanoparticles

15 ml of 1 mm diameter zirconia beads were placed in a 30 ml bottle, and 0.6 g of naproxen (TCI, M1021), 0.1 g of hydroxypropyl cellulose (Sigma Aldrich) and 6.8 g of water were injected as shown in Table 1 below. It was.

Subsequently, wet grinding was performed for 3 days at 100 rpm using a ball miller (Daejin Science) to prepare drug-containing nanoparticles according to Preparation Example 1.

Preparation Examples 2 to 6 Preparation of Drug-Containing Nanoparticles

Drug-containing nanoparticles according to Preparation Examples 2 to 6 were prepared by the same method as Preparation Example 1, except that the drug and the carrier were injected according to the composition shown in Table 1.

Production Example 7 Preparation of Mold

0.65 ml of heat-melt ethyl stearate was added to a 1.5 ml centrifuge tube (Axygen Scientific, MCT-185-C), melted at a temperature of 33 ° C., and a microneedle-shaped disk was injected thereon. It was quenched for 4 hours at a temperature of -17 ° C.

The mold was then prepared by separating and removing the microneedle disc from the solidified hot melt material.

Examples 1 to 6 Preparation of Microneedle

After adding hydroxy propyl cellulose, lactose and polyvinyl alcohol (PVA) so that the drug-containing nanoparticles obtained in Preparation Examples 1 to 6 were each shown in Table 2 below, the molds obtained in Preparation Example 7 were It was put in a centrifuge tube, which was centrifuged for 20 minutes at a speed of 8,000 rpm at a temperature of 6 ℃ and vacuum dried for 3 days.

After the vacuum drying of the solution containing the drug-containing nanoparticles in the form of a micro-needle, after dissolving the heat-melt material at a temperature of 50 ℃, the micro-needle comprising the prepared drug-containing nanoparticles Removed from the centrifuge tube and dried at room temperature for 5 hours.

As a result, each of the microneedle according to Examples 1 to 6 was prepared, the composition of each component contained in the microneedle according to Examples 1 to 6 is shown in Table 2 below, the electron microscope of the microneedle according to Example 1 The photo is shown in FIG. Naproxen in Table 2 means the drug-containing nanoparticles prepared in Preparation Examples 1 to 6.

Experimental Examples 1 and 2 Strength and Modulus Measurement Experiment

The mechanical strength of the microneedle prepared according to Examples 1, 3 and 6 was measured. To this end, according to the component compositions of Examples 1, 3 and 6 was prepared in the same manner as the microneedle manufacturing method in a disk model of diameter 15 mm, thickness 7 mm. The dried disk model was subjected to compression testing at a speed of 1 mm / min using an Instron Universal Testing 5942 instrument.

Figure 3 shows the compressive strength test results of the microneedle of Examples 1, 3 and 6.

In addition, the modulus was measured at the point of 10% deformation in the compressive strength test, and is shown in Table 3.

Comparing Examples 1 and 3, it can be seen that lactose has more influence on increasing mechanical strength than HPC.

In addition, in the case of Example 6, it can be seen that a high elasticity of 1.2 MPa can be obtained even at a drug content of 66 parts by weight.

According to a previous study (Jung-Hwan Park, Mark G. Allen and Mark R. Prausnitz, 'Polymer Microneedles for Controlled-Release Drug Delivery', Pharmaceutical Research , vol 23, p1008-1019), the loading of the drug is usually 10 parts by weight. The present invention is possible to load up to 66 parts by weight, but in this case the strength is also possible up to 1.2 MPa, it is possible to control the mechanical strength in a wide range.

In addition, in the case of mechanical properties, it is difficult to make a direct comparison according to a measuring method and the like, and the microneedle is broken and remains on the skin to deliver the drug only after penetrating the skin. The strength obtained in the present invention is 14-58.8 kPa (YP Zheng, MEMBER, and FT Mak, 'Extraction of Effective Young's Modulus of Skin and Subcutaneous Tissues from Manual Indentation Data', Proceedings-19th International Conference-IEEE) / EMBS Oct. 30-Nov. 2, 1997 Chicago, IL.USA) is judged to be 10 times stronger than the physical properties that can easily penetrate the skin, as shown in Figure 3, easily less than 100% strain ( It can be seen that the fracture is easy in strain).

10: heat meltable material 11: micro needle pattern
30: microneedle-shaped disc 50: drug-containing nanoparticles
100: micro needle 110: micro needle tip

Claims (9)

Forming a microneedle by applying a solution containing drug-containing nanoparticles to a mold having a microneedle pattern formed thereon; And
A second step of melting and removing the mold from the microneedle formed in the first step,
Melting point of the mold 20 to 60 ℃ a microneedle manufacturing method comprising a heat-melt material.
delete The method of claim 1,
The heat-soluble material comprises a microneedle, at least one selected from the group consisting of polyalkylene glycol, alkyl stearate and polydialkylsiloxane.
The method of claim 1,
Melting of the second step is a method of producing a microneedle heat treatment for 1 to 12 hours at a temperature of 30 to 70 ℃.
delete delete delete delete delete

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