KR20170132087A - Bleomycin-containing microneedle patch for treating warts and method for manufacturing the same - Google Patents

Abstract

The present invention relates to a microneedle patch which comprises a microneedle array comprising a pad base and a plurality of microneedles protruding from the pad base, and a drug coating unit containing bleomycin in the concentration of 100 g/cm^2 or higher on the microneedles; and to a method for manufacturing the microneedle patch.

Description

Micro-needle patches containing bleomycin for treating warts and methods of making same

The present invention relates to a micro needle patch and a method of making the same. More particularly, the present invention relates to microemia patches coated with bleomycin for the treatment of warts and methods of making the same.

Warts are infectious skin diseases that are caused by infection of the Human Papilloma Virus (HPV) and cause epidermal hyperproliferation on the skin or mucous membranes, leading to keratinization of the stratum corneum. HPV is distributed between the stratum corneum and the epidermis of the skin and can occur in various parts of the human body. Warts are most common in the hands and feet, but they cause problems in everyday life and cosmetics, depending on where they occur.

Twenty to thirty percent of warts are not responding well to treatment or recurrence. In children, fear of treatment is not enough to treat the disease. Treatment methods of warts include cryotherapy, CO ₂ laser treatment, electrocauterization, salicylic acid application, injection in bleomycin lesion, and surgical resection.

Injection therapy for bleomycin lesions is usually performed when the lesion is not cured properly and shows a cure rate of 47-83%. Bleomycin was extracted from Streptomyces verticillus and has antitumor, antimicrobial and antiviral functions. Injection therapy with bleomycin is performed by removing the hard flesh of the wart, diluting 15 mg of bleomycin into 5 ml and injecting it between the epidermis layer and the dermis layer using a 30 gauge needle (0.305 mm x 12.7 mm). The amount of injection varies depending on the size of the wart, for example, 0.2 ml for 5 mm, 0.5 ml for 10 mm, and up to 1.0 ml for larger than 10 mm.

On the other hand, when the size of warts is large or in several places, the dosage of bleomycin to be injected is increased, and it is troublesome to control the dose, and in addition, pain and discomfort are caused. In addition, administration of bleomycin with a conventional syringe has a problem in that the administration rate and dose of the drug are not constant, and a delicate injection operation is required because it is injected locally between the epidermis layer and the dermis layer. In addition, as with other warts, bleomycin intramedullary therapy has been a major obstacle to effective treatment because it causes fear of pain in all patients, not just children.

Therefore, there is a need in the art for a method that can solve both the dose delivery of drugs and the convenience of patients for effective treatment of warts.

The present invention provides a microneedle patch having a microneedle capable of minimizing pain with a delivery system having a shorter injection length into the skin than a general injection through a microneedle and delivering the drug to a desired skin layer and a method of manufacturing the same .

In addition, the present invention relates to a micro-organism capable of delivering bleomycin to a granular layer in which wart viruses are proliferated quantitatively by minimizing fear and rejection of treatment caused by pain by combining microneedle and bleomycin, A needle patch and a manufacturing method thereof.

According to an aspect of the present invention, there is provided a micro needle array comprising a pad base and a plurality of micro needles protruding from the pad base; And a drug coating comprising a bleaching agent on the micro needle at a concentration of at least about 100 μg / cm ² .

In one embodiment, the length of the microneedles may be at least about 400 microns.

In another embodiment, the microneedle array is one or more biodegradable selected from the group consisting of poly (lactic acid), poly (L-lactic acid), poly (glycolic acid), and poly (lactic-co- glycolic acid) And may be formed of a high-molecular-weight polymer.

In another embodiment, the microneedle array may have a tensile modulus of at least about 2.5 GPa and a tensile strength of at least about 50 MPa.

In another embodiment, the drug coating can be formed by dip coating the array of microneedles into a solution containing bleomycin.

In yet another embodiment, the drug coating may further comprise a thickener to increase viscosity and allow the drug to be coated on the microneedles in a non-flowing manner.

In another embodiment, the thickener may be carboxymethylcellulose or a salt thereof.

In another embodiment, the solution may comprise about 15% (w / w) of bleomycin and about 8% (w / w) of carboxymethylcellulose or a salt thereof.

In another embodiment, the drug coating can be coated with bleomycin to a position of about 40% to 50% from the tip end of the micro needle.

According to another aspect of the present invention, there is provided a method of manufacturing a micro-needle array, comprising the steps of: (a) fabricating a micro needle array having a pad base and a plurality of micro needles protruding from the pad base by a molding process; (b) treating UV and Ozone on the surface of the micro needle; And (c) immersing the array of microneedles in a solution containing bleomycin and drying the microneedle array.

In one embodiment, the microneedle array comprises at least one biodegradation selected from the group consisting of poly (lactic acid), poly (L-lactic acid), poly (glycolic acid) And may be formed of a high-molecular-weight polymer.

In another embodiment, step (a) comprises the steps of: (i) adding poly (lactic acid), poly (lactic acid), poly (glycolic acid), and poly (lactic-co-glycolic acid) to a microneedle array mold (Ii) melting the biodegradable polymer by heating the mold loaded with the biodegradable polymer, and (iii) drying the biodegradable polymer at room temperature to dry the biodegradable polymer at room temperature. , And isolating the micro needle array to obtain a micro needle array.

In another embodiment, between step (ii) and step (iii), the step of filling the molten biodegradable polymer into a hole formed in the microneedle array mold comprising the molten biodegradable polymer under reduced pressure conditions is added As shown in FIG.

In another embodiment, the solution containing the bleomycin may further comprise a thickener, preferably about 15% (w / w) of bleomycin and about 8% (w / w) of carboxymethylcellulose Or a salt thereof.

In another embodiment, step (c) can be performed by soaking in a solution containing bleomycin at a position of about 40% to 50% from the tip end of the microneedle and drying.

In another embodiment, the immersion and drying process of step (c) may be performed a plurality of times (e.g., three times immersing and drying at 15 minute intervals).

According to the present invention, it is possible to effectively remove warts while simultaneously reducing pain and fear in the treatment of warts.

In addition, the microneedle patch can contain a fixed amount of drug, and can deliver a fixed amount of drug to the wart formation site.

In addition, the microneedles have excellent mechanical strength to penetrate the thick stratum corneum and effectively deliver the drug.

In addition, the patient's discomfort can be minimized, and the convenience of the patient can be improved.

FIG. 1 is a schematic view showing steps of manufacturing a micro needle patch according to an embodiment of the present invention.
2 is a schematic view showing a part of a method of manufacturing a micro needle patch according to an embodiment of the present invention.
3 is an SEM image of a micro needle patch according to an embodiment of the present invention.
4 is a view showing a result of mechanical strength test of a micro needle patch according to an embodiment of the present invention.
5 is a schematic diagram of a process for treating warts using a micro needle according to an embodiment of the present invention.

Hereinafter, specific embodiments of the present invention will be described in detail with reference to the drawings. However, the spirit of the present invention is not limited to such embodiments, and the spirit of the present invention may be proposed differently by adding, modifying and deleting constituent elements constituting the embodiment, .

The present invention relates to a micro needle array (10) comprising a pad base (11) and a plurality of micro needles (12) protruding from the pad base (11); And a drug coating 13 on the micro needles 10 that contains bleomycin at a concentration of at least about 100 [mu] g / cm < ² >. The concentration of the bleomycin is clinically necessary for treating warts, and may be in the range of preferably 100 to 1,000 μg / cm ² , more preferably 400 to 600 μg / cm ² .

Also, in this case, microemia may include bleomycin at a dose of 100 ug / cm 2 or more, which is the amount of bleomycin clinically required to treat warts.

FIG. 1 is a schematic view showing steps of a method of manufacturing a micro needle patch according to an embodiment of the present invention, and FIG. 2 is a schematic view showing a part of a method of manufacturing a micro needle patch according to an embodiment of the present invention. 1 and 2, a method of manufacturing a micro needle patch 1 according to an embodiment of the present invention includes the steps of: (a) providing a pad base 11 and a plurality of micro needles Fabricating a microneedle array (10) having a cavity (12) by a molding process; (b) treating UV and Ozone on the surface of the micro needle 12; And (c) immersing the microneedle array 10 in a solution containing bleomycin and drying.

In the step (a) of fabricating the microneedle array 10 by a molding process, the microneedle array 10 may be performed using a microneedle array mold. For example, a biodegradable polymer is loaded onto a microneedle array mold 50 prepared from a microneedle master structure using Polydimethylsiloxane (PDMS, Sylgard 186, Dow Corning, MI), and a vacuum oven (EYELA, Tokyo The micro needle array 10 can be manufactured by melting the biodegradable polymer by using a mold 50 and then drying and solidifying the biodegradable polymer at room temperature and separating the micro needle array 10 from the mold 50 have. That is, step (a) includes the steps of (i) loading the biodegradable polymer into the microneedle array mold 50, (ii) heating the mold loaded with the biodegradable polymer to melt the biodegradable polymer, and (iii) drying the biodegradable polymer at room temperature and then separating the biodegradable polymer to obtain a microneedle array 10.

If desired, step (a) may further comprise filling the biodegradable polymer into the mold 50 cavity under reduced pressure conditions. That is, in one embodiment of the present invention, between step (ii) and step (iii), the molten biodegradable polymer is injected into the hole formed in the mold of the microneedle array containing the molten biodegradable polymer under reduced pressure May further include a filling step. The depressurization condition may be performed at, for example, -70 kPa, but is not limited thereto.

The microneedle arrays 10 may be made of poly (lactic acid) (PLA, Lakeshore Biomaterials, Birmingham, AL), poly (L-lactic acid) lactic-co-glycolic acid (PLGA), which is a biodegradable polymer.

The microneedle array 10 requires mechanical strength to penetrate the stratum corneum through the nature of warts. If the mechanical strength of the microneedle array 10 is sufficient, the microneedle array 10 can penetrate the skin without bending and bending phenomenon. However, if the microneedle array 10 has a low mechanical strength value, successful skin penetration may be difficult. That is, the microneedle array preferably has a tensile modulus of at least about 2.5 GPa and a tensile strength of at least about 50 MPa. For example, when a microneedle array is formed with an L-PLA having a molecular weight of about 100,000, it has a tensile strength of 55 to 82 MPa and a tensile modulus of 2.8 to 4.1 GPa, Can be used. The microneedle arrays formed from low molecular weight PLGA exhibited a tensile strength of about 40 MPa and a tensile modulus of about 1.4 GPa. Therefore, the micro needle array 10, particularly the micro needle 12, is preferably formed of PLA or L-PLA.

The microneedle array 10 manufactured by the above-described method includes a pad base 11 and a plurality of microneedles 12 protruding vertically from the pad base 11, for example. A tip is formed at the tip end of the micro needle 12. The pad base 11 and the microneedles 12 may be formed as one body and the number of the microneedles 12 may be approximately 100 on the pad base 11. However, the present invention is not limited thereto. The microneedles 12 may be formed in a pyramid shape. For example, the microneedles 12 may have a pyramid shape with a base of about 250 μm and a height of about 600 μm. The length (or height) of the micro needle 12 may be about 400 μm or more, preferably 400 to 1,000 μm, more preferably 500 to 8000 μm, and particularly preferably about 600 μm.

The surface of the biodegradable polymer can be changed to be hydrophilic by treating UV and Ozone on the surface of the micro needle 12 (step (b)). That is, the biodegradable polymer can be biodegradable by the process of step (c) The hydrophilic drug can be uniformly coated on the surface of the micro needle 12 by changing the property of the surface of the polymer from hydrophobicity to hydrophilicity. The UV / Ozone treatment can be performed using a UV-ozone cure system (MT-UV- Minuta Tech, Korea) apparatus at about 16 W for about 3 minutes.

Step (c) is carried out by immersing the microneedle array 10 in a solution containing the bleomycin and drying. The immersion and drying process may be performed a plurality of times (e.g., three times immersing and drying at 15 minute intervals). For example, bleomycin may be contained in the microneedle well 20 and coated onto the microneedle 10 using a dip-coating method. The microneedle well 20 may be formed in a shape corresponding to the microneedle array 10 and may include a partition wall 22 for receiving the well base 21 and the bromomycin coating solution 24.

The bleomycin coating solution 24 may further comprise, in addition to bleomycin, a thickener that increases viscosity and allows coating of the drug in the micro needle without coating. The thickening agent may be carboxymethyl cellulose (CMC) or a salt thereof (e.g., carboxymethyl cellulose sodium salt, CMC sodium salt).

In one embodiment, sodium CMC 4% (w / w) and bleomycin 16% (w / w) [Formulation A] in aqueous medium (i.e., distilled water); Sodium CMC 8% (w / w) and bleomycin 15% (w / w) [Formulation B]; 11% (w / w) sodium bromide and 15% (w / w) bleomycin [Formulation C]; And 14% (w / w) sodium CMC and 14% (w / w) bleomycin [Formulation D]. Table 3 shows the results of comparing the coating amount of the drug according to the CMC content after 3 times of immersion coating.

Formulation Number of dipping Coated bleomycin (ug) A 3 62.89 + - 6.82 B 3 518.12 + - 46.68 C 3 349.43 ± 17.6 D 3 213.79 ± 37.9

From the results shown in Table 1, when the content of sodium CMC was 4% (w / w), the amount of coated bromomycin was 62.89 6.82 ug. When the content of sodium CMC was 8% (w / The amount of bleomycin was significantly increased to 518.12 ± 46.68 ug. When the content of sodium CMC was 11% (w / w) and 15% (w / w), the amount of coated bromomycin decreased to 349.43 ± 17.6 ug and 213.79 ± 37.9 ug, respectively , Which is thought to be due to high viscosity. Therefore, it is preferable that the drug is finally evenly coated on the micro needle needle 12, and for effective bleomycin coating, it contains about 8% of CMC or its salt. That is, the coating solution preferably comprises about 15% (w / w) of bromomycin and about 8% (w / w) of carboxymethylcellulose or a salt thereof.

The microneedles 12 of the microneedle array 10 can be dip-coated into the coating solution a plurality of times at predetermined time intervals with each coating solution 24. [ For example, the microneedles 12 of the microneedle array 10 can be dip-coated three times in the coating solution 24, and when the microneedles 10 are immersed 3 times, To give a drying time. The drug coated three times on the micro needle 12 has a thicker coating thickness than other micro needles coated once, so that the coated drug can be dried after final drying (for example, after 3 times of immersion ) Is preferably performed for 24 hours or more.

When the micro needle 12 of the micro needle array 10 is immersed in the coating solution a number of times as described above, the drug coating portion 13 is formed on the outer surface of the micro needle 12 of the micro needle array 10. The drug coating 13 comprises bleomycin and may be coated with about 60% to 50% of the polyoma from the tip end of the micro needle. This is important for drug delivery. That is, when the drug is coated on the entirety of the micro needle 12 of the micro needle array 10, a difference may occur between the coating amount and the delivery amount.

In order to confirm quantitative and quantitative delivery of bleomycin coated on the micro needle 12, bleomycin coated on the micro needle 12 was dissolved and quantified with a nano drop. When the micro-needle 12 was immersed once in the Formulation B coating solution, 65.97 ± 5.8 μg of bleomycin was coated on all 100 micro-needle arrays 10, and 215.55 ± 24.01 μg, and 518.12 ± 46.6 μg of bleomycin was coated in the case of 3 times of immersion.

3 (a) is an SEM image of a micro needle array before coating, Fig. 3 (b) is an SEM image of a microneedle array coated once with bleomycin, and d in Fig. 3 is a micro needle 3 is a low magnification SEM image of a microneedle array coated three times with bleomycin. Referring to FIG. 3, in the coating method of the bromomycin drug, only the tip ends (i.e., the micro needles) of the micro needle array 10 are immersed in the drug by the dip coating method as described above, It is preferable that the drug be uniformly coated to a position of about 40% to 50% from the tip end of the drug.

A thin layer of drug is coated on the tip of the microneedle immersed in the coating solution once (see Fig. 3b), and the microneedles immersed twice in the coating solution are slightly thicker than the microneedles immersed once . The microneedles which were immersed three times had the thickest drug coated and the bottom portion of the coating had a thick and thick shape (Fig. 3d). 3 ', the drug is uniformly coated on the micro needle positioned at the edge. That is, as the number of microneedles is increased, the amount of drug coated on the microneedles increases. It is also confirmed that the drug is uniformly coated on 100 micro needles.

The first drug coating was well coated with the drug on the hydrophobic micro-needle 12 due to the hydrophilic conversion of the surface due to the UV / Ozone coating, and from the second coating hydrophilic interactions between the already coated surface and the drug, The adhesion of the drug results in a thick, uniform coating surface on the micro needle.

4 is a view showing a result of mechanical strength test of a micro needle according to an embodiment of the present invention. 4A shows the shape of the PLGA micro needle after pricking the pig skin with a force of 30 N, FIG. 4A 'shows the shape of the PLA micro needle after pricking the pig skin with 30N, Is a form of pig skin dyed with a tree leaf blue after stabbing a pig skin with a PLA microneedle with a force of 30N. 4B shows the PLA micro needle after poking the pig skin with 40N, and b 'in FIG. 4 shows the PLA micro needle after sticking the pig skin with 40N. Fig. 4B' Is a form of pig skin dyed with tree pan blue after stabbing pig skin with PLA microneedle with a force of 40N.

Each microneedle made with L-PLA and 50:50 Poly (DL-lacide-co-glycolide) (PLGA, LACTEL, Birmingham, AL) was used to test whether the micro needles had the strength to penetrate the thick skin layer of the warts The pork skin was stabbed to confirm the suitability of the micro needle in the wart skin. Micro-needles made of PLGA and L-PLA were prepared to confirm that the micro needle was successfully stuck onto the skin of the pig according to the mechanical strength of the polymer. The microneedles were placed on each skin and pressed with a force of 30N and 40N for 2 minutes using a skin pressure device. The skin was then stained with a trypan blue 0.4% (Sigma-Aldrich) solution for 5 minutes on top of the microneedled skin. After removing the blue triplane solution, the number of points was counted by using an optical microscope. The morphology of the micro needle was confirmed by SEM after needle stabbing on the skin.

The micro needle made from PLGA failed to withstand the force from 30N, the micro needle collapsed and the micro needle was not stuck in the skin, and the micro needle array also started to break (Fig. 4a). On the other hand, the micro needle made of PLA permeated the skin without bending and breaking (a 'in FIG. 4). Using a micro needle made of PLA, a thick pork skin insert resulted in 52.7 ± 8.7 holes in a total of 100 needles.

At 40N, the PLGA needles broke into many pieces and did not staple the needles, but just crushed (Fig. 4b). The needle of the PLA pierced the skin, and no warp of the needle appeared (b 'in Fig. 4). This is because the needles are pressed with a strong force to penetrate the stratum corneum of the skin, allowing the needles to pass through the skin without bending. When a force of 40 N was applied, 72.7 ± 2.5 skin penetration holes were formed in a total of 100 needles. As a result, in the case of thick skin tissues, PLA needles penetrated through the skin without collapsing and bending than PLGA needles.

Both PLA and PLGA microneedles penetrated the skin without breaking and bending on normal skin, but PLA needle was well permeated without breaking on skin with thick stratum corneum. This indicates that the skin has a mechanical strength that can be penetrated in any skin regardless of the thickness of the skin. Warts occur regardless of the skin area of a person, starting from the thin mouth mucosa to the soles with thick stratum corneum. Micro-needles made of PLA are particularly suitable for wart treatment because they have the strength to penetrate the skin layer no matter where they occur on the body.

The delivery of bleomycin drug through the micro needle was confirmed by the delivery of a larger amount of drug with longer patch delivery time. 5, the bleomycin delivered to the skin was 383.57 ± 1.57 ug / 100 needles, showing a transfer efficiency of 74.03% of the drug coated on the skin when the micro needle was pinched for 10 minutes, As a result, the delivery time of 426.47 ± 10.44 ug / 100 needles was 82.31% of total drug delivery. That is, most of the bleomycin is delivered to the skin at the administration time of 15 minutes or more.

The microneedle patches obtained according to the present invention can laminate a conventional support layer under the pad base. The support layer may be a release liner commonly used in the field of percutaneous absorption preparation or a laminate thereof. For example, a polyethylene resin, a polyester resin, a polyvinyl chloride, a polyvinylidene chloride Or a laminate thereof may be used.

The microneedle patch obtained according to the present invention can also laminate a protective film for protecting the microneedles on the microneedle array. The protective film may be a drug-absorptive and flexible material commonly used in the field of percutaneous absorption preparations. Examples of the protective film include polyolefins, polyethers, multi-layer ethylene vinyl acetate films, layer ethylene vinyl acetate film, polyester, and polyurethane.

Claims (17)

A micro needle array comprising a pad base and a plurality of micro needles protruding from the pad base; And
Drug coating comprising a bleomycin to about 100 μg / cm ² or more concentration on the microneedle
/ RTI > The microneedle patch of claim 1, wherein the length of the microneedles is greater than or equal to about 400 microns. The method of claim 1, wherein the microneedle array is one or more selected from the group consisting of poly (lactic acid), poly (L-lactic acid), poly (glycolic acid) Micro needle patch formed of biodegradable polymer. The micro needle patch of claim 1, wherein the microneedle array has a tensile modulus of at least about 2.5 GPa and a tensile strength of at least about 50 MPa. 2. The micro-needle patch of claim 1, wherein the drug coating is formed by immersing the array of microneedles in a solution containing bleomycin. The microneedle patch of claim 5, wherein the solution further comprises a thickener. 7. The microneedle patch of claim 6, wherein the thickener is carboxymethylcellulose or a salt thereof. 6. The micro-needle patch of claim 5, wherein the solution comprises about 15% (w / w) of bromomycin and about 8% (w / w) of carboxymethylcellulose or a salt thereof. The micro needle patch of claim 1, wherein the drug coating is coated with bleomycin to a position of about 40% to 50% from the tip end of the micro needle. (a) fabricating a micro needle array having a pad base and a plurality of micro needles protruding from the pad base by a molding process;
(b) treating UV and Ozone on the surface of the micro needle; And
(c) immersing the array of microneedles in a solution containing bleomycin and drying
Wherein the micro needle patch comprises a plurality of micro needle patches. The method of claim 10, wherein the microneedle array is one or more selected from the group consisting of poly (lactic acid), poly (L-lactic acid), poly (glycolic acid) Method of making micro needle patch formed of biodegradable polymer. 12. The method of claim 11, wherein step (a) comprises: (i) adding poly (lactic acid), poly (lactic acid), poly (glycolic acid), and poly (lactic-co- glycolic acid) , Loading one or more biodegradable polymers selected from the group consisting of < RTI ID = 0.0 >
(ii) heating the biodegradable polymer-loaded mold to melt the biodegradable polymer, and
(iii) drying the biodegradable polymer at room temperature, followed by separation to obtain a microneedle array. 13. The method of claim 12, further comprising, between step (ii) and step (iii), filling the molten biodegradable polymer into a hole formed in the mold of the microneedle array comprising the molten biodegradable polymer under reduced pressure conditions Wherein the micro needle patch comprises a plurality of micro needle patches. 11. The method of claim 10, wherein the solution containing the bleomycin further comprises a thickener. 15. The method of claim 14, wherein the solution containing the bleomycin comprises a micro needle patch comprising about 15% (w / w) of bleomycin and about 8% (w / w) of carboxymethyl cellulose or a salt thereof . 11. The method of claim 10, wherein step (c) is performed by soaking in a solution containing bleomycin at a position of about 40% to 50% from the tip end of the micro needle and drying. 17. The method of claim 10 or 16, wherein the immersion and drying step of step (c) is performed a plurality of times.

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