KR101613008B1 - Microbullet for drug delivery - Google Patents

Abstract

The present invention relates to a drug delivery micro-bullet in which a bullet containing a drug is separated from the base by an external force and inserted into the skin.
The micro-bullet of the present invention can be inserted into the skin only from the base of the bullet, so that a desired amount of drug can be dosed without loss. In addition, the micro-bullet of the present invention can control the depth of administration of the bullet according to the magnitude of the transmitting force. The present invention is a method in which a conventional transdermal delivery system requires a long administration time, while delivering a desired amount of drug to the skin layer within a few seconds. The micro-bullet of the present invention is capable of inserting a drug into the bullet structure, and can control the release rate and amount of the drug in the skin according to the size of the bullet, the biodegradation rate of the bullet, and the like.
Since the micro-bullet of the present invention has a bullet attached to the base and the bullet is separated at the same time as the penetration of the skin by the external force, 1) hundreds or thousands of bullets can be transmitted by one external force and 2) mg to several tens of mg of drug per day. Also, since the bullet is attached to the base and is handled with a film-type base, it is easy to handle, exists in a film form and is easy to connect with a conventional patch formulation, and does not require a complicated device such as a cylinder for bullet administration, The force transfer system is simple because only the force required to separate it from the bullet is applied.

Description

Microbullet for drug delivery < RTI ID = 0.0 >

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a bullet for drug delivery, and more particularly to a drug delivery micro-bullet in which a bullet containing a drug is separated from the base by an external force and inserted into the skin.

Currently, commercialized drug delivery systems are largely divided into oral preparations, injections, and transdermal preparations. Among them, oral administration is the most common and convenient method, but it causes limitation of drug degeneration and absorption due to gastrointestinal tract, and most of proteins and DNA constructs such as insulin and hormone drugs are decomposed by the gastrointestinal tract and are difficult to be effectively used.

Injection is also the fastest and most effective method of drug delivery, but patient suffering and rejection of needles not only causes mental stress on the patient, but also requires the help of professional medical personnel and difficulties in repeated administration.

To overcome these disadvantages, new methods of transdermal administration have been developed. In the case of the transdermal drug delivery system, it is possible to avoid the gastrointestinal disorder by transferring the drug through the skin, and it is possible to reduce the pain and rejection of the patient when the drug is administered. However, in the case of transdermal drug delivery, the molecular weight of the drug delivered by the stratum corneum present in the outermost layer of the skin is only 500 Da or less, and there is a limit to an effective drug delivery system due to differences in the amount and rate of delivery depending on the type of drug .

In order to overcome this problem, new systems such as iontophoresis, electrophoresis, heating, microneedle, and chemical enhancer have been developed. However, there are limitations in transferring a sufficient amount of the drug.

In the case of the micro needle, the length of the drug can be adjusted to 90 ~ 1500 ㎛ according to the purpose of drug delivery by transmitting a drug through a small hole on the surface of the skin. This form is a physical puncture of the horny layer, which is the outermost layer of the skin, through which the drug is delivered. However, in the conventional microneedle system, since the hole formed is small in size and the hole of the skin is closed over time, it is difficult to transfer the dose, and in order to deliver the drug to the surface of the needle or the inside of the needle, The depth of penetration of the needle into the skin depends on the length of the needle as well as the condition of the skin, the force applied, and the user's method of use. In addition, slow release drug delivery is difficult and it is difficult to deliver nanocarriers such as nanoparticles, liposomes, etc., through holes that are formed.

[Prior Art]

1. US 7846488 B2 (Registered on December 7, 2010): Masking method for coating a microneedle array

2. US 2004/0106904 A1 (released June 3, 2004): Microneedle array patch

The present invention is to provide a microstructure capable of supplying drug in a desired amount as much as possible without loss.

The present invention provides a microstructure capable of injecting a fixed amount of drug.

The present invention provides a microstructure capable of controlling the depth of administration of a drug.

The present invention relates to the delivery of a desired amount of drug to desired depths in the skin within a few seconds

According to one aspect of the present invention, And a micro bullet which is formed on the base portion and includes at least one bullet having a sharp end containing a drug and is inserted into the skin when the bullet is separated from the base portion when an external impact is applied to the base portion.

The micro-bullet of the present invention can be inserted into the skin only from the base of the bullet, so that a desired amount of drug can be dosed without loss. In addition, the micro-bullet of the present invention can control the depth of administration of the bullet according to the magnitude of the transmitting force. The present invention is a method in which a conventional transdermal delivery system requires a long administration time, while delivering a desired amount of drug to the skin layer within a few seconds. The micro-bullet of the present invention is capable of inserting a drug into the bullet structure, and can control the release rate and amount of the drug in the skin according to the size of the bullet, the biodegradation rate of the bullet, and the like. That is, the micro-bullet of the present invention is capable of sustained-release delivery, and it is also possible to deliver localized transdermal delivery by controlling the administration site.

Since the micro-bullet of the present invention has a bullet attached to the base and the bullet is separated at the same time as the penetration of the skin by the external force, 1) hundreds or thousands of bullets can be transmitted by one external force and 2) mg to several tens of mg of drug per day. Also, since the bullet is attached to the base and is handled with a film-type base, it is easy to handle, exists in a film form and is easy to connect with a conventional patch formulation, and does not require a complicated device such as a cylinder for bullet administration, The force transfer system is simple because only the force required to separate it from the bullet is applied.

1 is a schematic view showing a micro-bullet according to an embodiment of the present invention.
Figure 2 is a side schematic view of Figure 1;
Figure 3 shows a micro-bullet which is another embodiment of the present invention.
4 is a schematic view showing the micro-bullet of FIG. 1 inserted into the skin;
5 is a schematic view showing the micro-bullet of FIG. 2 inserted into the skin;
Figure 6 shows that the air jet 7 inserts the micro-bullet into the skin with a liquid jet.
8 is an SEM image of the micro-bullet obtained in Example 2. Fig.
FIG. 9 is a photograph of the micro-bullet taken in the skin after inserting the micro-bullet in Example 8. FIG.
10 is a photograph (a) taken on the skin and a photograph taken on the side of the skin (b) after inserting the micro-bullet into the skin as in Example 9. FIG.
11 is a photograph (a) taken on the skin and a photograph (b) taken on the side of the skin after the micro-bullet is inserted into the skin as in the case of Example 10. Fig.

The present invention relates to a micro-bullet in which a drug-containing bullet is inserted into the skin.

FIG. 1 is a schematic view showing a micro bullet according to an embodiment of the present invention. FIG. 2 is a side schematic view of FIG. 1, FIG. 3 shows a micro bullet according to another embodiment of the present invention, FIG. 5 is a schematic diagram showing the insertion of the micro-bullet of FIG. 2 into the skin. FIG.

1 to 5, the micro-bullet includes a base portion 10 and a bullet 20.

The bullets are formed and arranged on the base portion 10. When the impact is applied to the base part, the connection part between the bullet and the base part is broken and separated from the bullet 20.

3, the base portion 10 may be formed on the fixing portion 30. As shown in FIG.

The fixing portion 30 may be formed by using an elastic polymer material without limitation. For example, poly-di-methyl-siloxane (PDMS) can be used as the fixing portion 30.

The bullet 20 can be detached from the base 10 and inserted into the skin when an external impact is applied to the fixing part 30.

The bullets 20 are formed on the base 10.

The bullet 20 may be contained in the drug or may be coated on the surface, so that the drug can be delivered into the skin.

The bullet 20 has a sharp-pointed structure to facilitate insertion into the skin. The bullet may have a horn structure, for example, a quadrangular pyramid or a conical structure.

The surface of the bullet can be etched to facilitate skin insertion. The etching can be performed using any known etching method without limitation, and preferably, dry etching, for example, reactive ion etching (RIE) can be used to reduce the surface roughness.

The external impact applied to the micro bullet may be a known liquid jet, an air jet or a pneumatic cylinder. Figure 6 shows that the air jet 7 inserts the micro-bullet into the skin with a liquid jet.

The impact applied to the micro-bullet may range from 0.1 to 10 kgf / cm 2, and the minimum pressure is a pressure at which the bullet can be separated from the base by the impact.

The maximum pressure is a pressure that allows the bullet to be inserted to a predetermined depth of the skin.

The thickness of the base portion may be 10 to 2000 탆, preferably 50 to 500 탆, more preferably 50 to 200 탆.

Porous pores (holes), irregularities, grooves, or patterns may be formed on the joint surfaces of the bullet and base so that the bullet is separated from the base part when an external impact is applied to the micro bullet.

The porous pores, irregularities, and grooves can be formed using any known wet or dry etching method, surface treatment method, and the like without limitation.

The base portion may be made of a brittle or porous structure which is easily broken so that the bullet can easily be broken down by the applied force and can be delivered subcutaneously. Alternatively, the base portion may be made of a tacky material such as PDMS such that the needle can be separated from the tacky base by the applied force Materials can be used.

Further, the base portion may be low-tacky silicone, polyurethane, hyaruronic acid, physical adhesive (gecko), polyacrylic, ethylcellulose, hardoxymethylcellulose, ethenylene vinyl acetate and polyisobutylene.

The breaking strength of the base portion may be 0.1 to 10 kgf / cm 2, preferably 0.1 to 2 kgf / cm 2.

If the base is an adhesive component, the adhesive force (viscosity) may be 0.1 to 10 kgf / cm 2, preferably 0.1 to 2 kgf / cm 2.

The base and the bullet may be the same or different materials.

The base and the bullet may be a biocompatible material, a water-soluble polymer, or a liposoluble polymer.

The bullet may be prepared by mixing the biocompatible material, the water-soluble polymer or the oil-soluble polymer constituting the bullet with the drug. In this case, the bullet may contain a stabilizer.

The biocompatible material may be selected from the group consisting of hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, (PGA), polylactide-glycolidide copolymer (PLGA), hyaluronic acid, alginic acid (< RTI ID = 0.0 > alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polyanhydride polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly (butyric acid), poly (valeric acid), poly But are not limited to, polyurethanes, polyacrylates, ethylene-vinyl acetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl fluorides, poly (vinylimidazoles), chlorosulphonate polyolefins Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethyl Cellulose, cellulose, cyclodextrin, copolymers of monomers forming such polymers, and cellulose.

Oligosaccharide, sucrose, maltose, lactose, cellobiose, or gentiobiose may be added to the base portion. In this case, the base portion is brittle and more likely to be broken, so that the bullet is easily separated.

Examples of the water-soluble polymer include polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, carboxymethylcellulose, hydroxyethylcellulose, xanthan gum, locust bean gum, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non- Polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylic acid, polymethacrylic acid, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulphonate polyolefins, A copolymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, cyclodextrin and monomers forming such a polymer. It may be composed of two or more substances.

The liposoluble polymer may be selected from the group consisting of hydroxy propyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), poly caprolactone (PCL), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), poly ethylene oxide (PEO) ), Polyvinyl methyl ether (PVME), poly (methyl acrylate) s, propylene glycol, poly ester amide, poly (butyric acid), acrylic amide, acrylic acid, hyaluronic acid gelatin. < / RTI >

In another aspect, the invention relates to a method of making the micro-bullet.

The method of manufacturing the micro-bullet can use any conventionally known methods without limitation. For example, Japanese Patent Application Laid-Open No. 2005154321 proposed by Nano Device & And " Sugar Micro Needles as Transdermic Drug Delivery System " (Biomedical Microdevices 7: 3, 185-188, 2005). Further, a method of producing a biodegradable polymer micro-needle by making a template by photolithography (Fabrication, mechanics and transdermal drug delivery, Journal of Controlled Release 104, 51-66, 2005) can be referred to.

In addition, an elastic mold such as polydimethylsiloxane (PDMS) can be manufactured by a known soft lithography technique and used for manufacturing a microstructure. The PDMS mold manufacturing technology is a kind of plastic processing technique, and a desired molding structure can be obtained by various methods such as casting, injection, hot-embossing, and the like. For example, a photosensitive material is coated on a substrate such as a silicon wafer or glass, and patterned using a photomask, resulting in a master. When the PDMS is cast and sintered with the mold, a PDMS mold having a stamp function can be completed.

The method includes the steps of injecting the material constituting the bullet into a hole of a micro-mold, for example a PDMS mold, and drying, and removing the micro-mold.

The material constituting the bullet can be referred to above.

And injecting the bullet forming material into the hole and coating the bullet forming material to a predetermined height on the mold surface. In this case, the bullet and base portion may be formed of the same material. However, in the case of manufacturing the base portion, it is preferable to coat the base portion without adding a drug or a stabilizer.

In the meantime, the micro-bullet manufacturing method of the present invention includes the step of injecting and drying the material constituting the bullet into the hole of the micro-mold, forming the base, and removing the micro-mold.

The method can form the bullet first, dry it, and form the base part thereon. In this case, the base portion may be coated with a material different from the bullet forming material.

For example, silicone, polyurethane, hyaruronic acid, a physical adhesive (gecko), polyacrylic, ethylcellulose, hardoxymethylcellulose, ethene vinyl acetate and polyisobutylene can be used as the base portion have.

The breaking strength of the base portion may be 0.1 to 10 kgf / cm 2, and the adhesive force (viscosity) may be 0.1 to 10 kgf / cm 2 when the base is a substance of an adhesive component.

And applying pressure to the base portion to adjust the thickness of the base portion to 50 to 500 mm to make the base portion thin.

Hereinafter, the present invention will be described in more detail with reference to examples, but these examples should not be construed as limiting the scope of protection of the present invention.

Example  One

The PDMS mold was filled with a powdery PLGA having a molecular weight of 50,000 kDa and a force of 3 kg / cm 2 was applied to the polymer melt on the surface of the mold to obtain a thickness of about 0.4 μm on the surface of the PDMS, ≪ / RTI > was obtained.

Subsequently, the micro-bullet was dip-coated on a 50-mM Kaltsin solution as a model drug, a calcine solution model drug, and a calcein solution was coated on the surface of the bullet

Example  2

The PDMS mold was filled with powdery PLGA having a molecular weight of 50,000 kDa, and the remaining polymer on the surface was removed. Then, 5% solution of polystyrene (PS) dissolved in ethylacetate was coated on the surface of the mold, And removed with a needle to give a micro-bullet.

Subsequently, the micro-bullet was dip-coated on a 50-mM Kaltsin solution as a model drug, a calcine solution model drug, and a calcein solution was coated on the surface of the bullet

Example  3

0.1 g of poly-caprolactome particles were placed on the PLGA base layer of Example 1 and coated in an oven. After heating at about 70 캜 for 30 minutes, 3 kg / cm 2 pressure was applied to obtain a micro-bullet in which a fixing part was formed.

Example  4

The microballs obtained in Example 3 were placed in an RIE chamber and RIE was performed under conditions of CF 4: O 2 = 10: 100, 100 W to make the bullets smoother and sharper. The base had a reduced mechanical strength due to the formation of fine holes .

Example  5

5 ml of 25% CMC, a water-soluble polymer, and 50 mM of a model drug, Calcine, were mixed and injected into the holes of the PDMS micro-mold. Subsequently, the polymer solution was filled in the mold with vacuum and dried for 3 hours while applying a pressure of 1 kgf / cm2. The CMC was coated on the surface of the micro mold with a base material to a thickness of 200 탆 and dried.

Example  6

trehalose (drug stabilizer) was mixed with the water-soluble polymer CMC at a ratio of 1: 1 and added to the model drug. The addition of trehalose makes the base brittle and more susceptible to breakdown, making it easier for the bullet to separate.

Example  7

The same procedure as in Example 5 was performed except that 5 ml of 25% HPMC, which is a liposoluble polymer, and 10 mM Rhodamine as a model drug were mixed in a hole of a micro-mold instead of a water-soluble polymer and CMC as a model drug.

Example  8

except that silicone was used instead of PS as base layer (silicone elastomer base and silicone elastomer curing agent were mixed at a ratio of 10: 1).

Example  9-11

The micro-bullets obtained in Examples 1 to 5 were contacted on the skin

liquid jet (using the micro bullets of Example 9-Example 5), air jet (using the micro bullets of Example 10-Example 1), pneumatic cylinder (using the micro bullets of Example 11-Example 1) Was used to pressurize the micro-bullet. The pressure was set to about 0.2 to 10 kg / cm 2.

8 is an SEM image of the micro-bullet obtained in Example 2. Fig. FIG. 9 is a photograph taken on the skin after inserting the micro-bullet into the skin in Example 9, FIG. 10 is a photograph (a) taken on the skin after inserting the micro-bullet into the skin as in Example 10, The photograph (b) taken. 11 is a photograph (a) taken on the skin and a photograph taken on the side of the skin (b) after inserting the micro-bullet into the skin as in Example 11. Fig. 9 to 12, it can be seen that the bullet is separated from the base and inserted into the skin.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments.

Claims (13)

A base portion;
And at least one bullet which is formed on the base portion and contains a drug and is formed in a pyramid or a conical structure, and when an external impact is applied to the base portion, the bullet is separated from the base portion and inserted into the skin The micro bullet. The micro-bullet according to claim 1, wherein the micro-bullet further comprises a fixing part made of an elastic polymer material, and the base part is formed on the fixing part. The micro-bullet according to claim 1, wherein the thickness of the base portion is 20 to 1,000 占 퐉. The micro-bullet according to claim 1, wherein the micro-bullet is formed with porous pores, concavities, convexities, grooves, or patterns on the joint surface of the bullet and base so that the bullet is separated from the base part when an external impact is applied. 2. The adhesive sheet according to claim 1, wherein the base portion is formed of silicon, polyurethane, hyaruronic acid, physical adhesive (gecko), polyacrylic, ethylcellulose, hardoxymethylcellulose, ethenylene vinyl acetate or polyisobutylene The micro bullet as. The micro-bullet according to claim 1, wherein the base has a breaking strength of 0.1 to 10 kgf / cm 2. The micro-bullet according to claim 1, wherein when the base is an adhesive component, the adhesive force is 0.1 to 10 kgf / cm 2. The micro-bullet according to claim 1, wherein the external impact is applied to the base portion using a liquid jet, an air jet, or a pneumatic cylinder at a pressure of 0.1 to 10 kgf / cm 2. The micro-bullet according to claim 1, wherein the base and the bullet may be the same or different materials. The micro-bullet according to claim 1, wherein the base and the bullet are formed of a biocompatible material, a water-soluble polymer, or a liposoluble polymer. 11. The method of claim 10 wherein the biocompatible material is selected from the group consisting of hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, , Collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), hyaluronic acid Alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, Polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly (butyric acid), polyacrylic acid, But are not limited to, poly (vinylidene chloride), poly (valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylmethylcellulose Wherein the microcapsule is at least one selected from the group consisting of cellulose (HPC), carboxymethylcellulose, cyclodextrin, a copolymer of monomers forming such a polymer, and cellulose. The method according to claim 5 or 11, wherein the base portion is formed of a material selected from the group consisting of trehalose, oligosaccharide, sucrose, maltose, lactose, cellobiose, A micro-bullet characterized by the addition of gentiobiose. The method of claim 10, wherein the liposoluble polymer is selected from the group consisting of hydroxy propyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), poly caprolactone (PCL), polyvinyl pyrrolidone (PVP), polyethylene glycol (PE) Poly (propylene glycol), poly (ester amide), poly (butyric acid), acrylamide (acrylic amide), acrylic acid, HA (hyaluronic acid), and gelatin.

Images