KR102494067B1 - Soluble microneedle patch containing measles vaccine ingredient - Google Patents

Abstract

The present invention relates to a skin administration system for a measles vaccine capable of stably impregnating the measles vaccine and effectively delivering it into the skin, thereby exhibiting excellent effects, and is characterized in that it is a microneedle containing a measles vaccine.

Description

Soluble microneedle patch containing measles vaccine ingredient}

The present invention relates to microneedles and microneedle patches.

Measles is caused by infection with the measles virus and is highly contagious, affecting more than 90% of susceptible contacts. Fever, runny nose, conjunctivitis, erythematous spots, and papules appear in combination and are characterized by a disease-specific mucosal eruption. Measles vaccine is a vaccine to prevent measles. In the first dose, an inactivated vaccine is injected into the muscle or under the skin, and in the second dose, a live attenuated vaccine can be inoculated under the skin after 4 to 6 weeks. also inoculate.

On the other hand, vaccination is a cost-effective way to prevent infectious diseases. Numerous new vaccines such as proteins, polysaccharides, and DNA are being developed to prevent infectious diseases more efficiently, and the most common method of vaccination is oral. It is known to inject into other parts of the body.

However, needle phobia, unpleasant pain, and localized skin and muscle damage caused by needle injection, as well as hepatitis B and C, hepatitis B and C, There is a risk of being infected with infectious diseases such as human immunodeficiency virus.

As another vaccination method, there is a vaccination method through the nasal cavity, but there are problems such as low bioavailability, relatively high cost, and sudden facial paralysis (Bell's palsy).

Therefore, there is a need for a new method that can be effectively used for measles vaccination without side effects.

Republic of Korea Patent Publication No. 10-2014-0125364

The problem to be solved by the present invention is to provide a system for stably impregnating a measles vaccine into soluble microneedles and effectively delivering the measles vaccine into the skin and a method for manufacturing such a system.

Accordingly, the present invention provides soluble microneedles comprising a measles vaccine.

In addition, the present invention provides a microneedle patch including the microneedles.

In addition, the present invention provides a method for preparing a microneedle containing a measles vaccine.

In order to solve the above problems, the present invention provides soluble microneedles containing a measles vaccine, and more preferably, the material forming the microneedles is dissolved in the skin so that the microneedles dissolve or dissolve when the microneedles are applied to the skin. Disruption causes the measles vaccine to be released into the skin.

After a long period of research, the present inventors impregnated the measles vaccine into soluble microneedles so that the measles vaccine was effectively delivered into the skin, and the measles vaccine was supplied to the vicinity of dendritic cells in the skin to provide an excellent measles preventive effect through more rapid antigen present. In addition, in the case of conventional injection inoculation, it was confirmed that there is no concern about pain and / or side effects caused by the injection needle, and the present invention was completed.

As used herein, the term "measles vaccine" includes both approved and non-approved measles vaccines, and may include both live and inactivated vaccines, but is not limited thereto, Edmonston, Schwartz, Moraten, AIK-C, Edmonston-Zagreb, Cam-Kovax (Tanabe), and the like.

The present inventors have studied various administration systems and none of the systems are similar to the method of impregnating the soluble microneedles of the measles vaccine. After several efforts, the present inventors made a surprising invention that confirmed a remarkable effect without side effects by impregnating a measles vaccine into a microneedle. In addition, if the microneedles other than the present invention are used, measles vaccine can be easily administered without side effects in a non-invasive manner even to unskilled ordinary people, and since all vaccines can be delivered intradermally, excellent effects can be exhibited.

As used herein, the term "impregnation" may refer to a form in which the measles vaccine can be contained in the microneedles, and preferably i) contains the measles vaccine together with the soluble material forming the microneedles (microneedle structure measles vaccine dispersed within), or ii) microneedles may be pierced to contain the measles vaccine in the hole. When the microneedles are prepared in the form of i) and ii), the measles vaccine can effectively penetrate into the skin, and it is preferable to prepare the microneedles in the form of i), in particular, the measles vaccine is dispersed in the microneedle structure It is preferred that it is in the form of

Therefore, it is most preferable that the substance forming the microneedles is dissolved in vivo so that the measles vaccine contained in the microneedles is effectively released into the skin.

In a preferred embodiment of the present invention, the material forming the microneedles is dissolved in the skin, so that the microneedles dissolve or collapse when the microneedles are applied to the skin, so that the measles vaccine contained in the microneedles can effectively penetrate into the skin. can

In the present invention, the microneedles may preferably be soluble in the skin, and to form soluble microneedles, for example, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC, Sodium carboxymethyl cellulose) , water-soluble polymers such as vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used. In particular, considering the skin penetration strength of the microneedle and the dissolution rate in the skin comprehensively, hyaluronic acid, sodium carboxymethyl cellulose (Na-CMC), and saccharide (preferably is preferably a mixture of trehalose), and more preferably a mixture of glycerin.

Preferably, the microneedles of the present invention may additionally include a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, and the like in addition to the above components forming the microneedles.

As the plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin are used alone. or may be used in combination.

Although the length of the microneedles according to the present invention is not limited to a specific size, it is preferable to apply them within a range that does not come into contact with nerves and blood vessels because pain and drug delivery efficiency may be affected when the microneedles are applied. . Therefore, the length of the microneedle according to the present invention is not limited thereto, but may preferably be about 200 to 500 μm.

In the present invention, the measles vaccine may be included in 0.00001 to 1% by weight, preferably 0.0001 to 0.5% by weight, more preferably 0.001 to 0.1% by weight based on the total weight of the microneedles. When included in less than 0.00001% by weight, an effective effect may not be exerted, and when included in more than 1% by weight, side effects may occur or the physical properties and durability of microneedles may be affected, which is undesirable.

When the microneedle according to the present invention is applied to the skin, the amount of skin penetration can be remarkably improved compared to other conventional skin administration systems.

In addition, the present invention provides a microneedle patch including the microneedles, that is, a microneedle patch for measles vaccine administration (or delivery) to which the microneedles are attached.

In the present invention, the patch may refer to a sheet to which one or more microneedles impregnated with the measles vaccine of the present invention are attached and the surface to which the microneedles are attached can be attached to the skin. The size of the sheet is not limited to a specific size, and may be appropriately adjusted according to the amount of measles vaccine to be absorbed into the skin or the attachment site. In addition, one or more, preferably a plurality of microneedles may be attached to the surface of the sheet attachable to the skin.

In addition, the surface of the patch that can be attached to the skin can also contain the measles vaccine so that the measles vaccine can penetrate the hole formed by the microneedles, and the measles vaccine is impregnated into the microneedles to achieve an excellent skin administration effect. It is desirable to do

In addition, the present invention comprises the steps of S1) filling and mixing a material for forming microneedles including a measles vaccine and a material soluble in the skin in a mold; And S2) provides a method for producing a microneedle containing a measles vaccine comprising the step of warming and drying the mold and separating it.

The method can be prepared by impregnating the measles vaccine into microneedles, and the impregnation is preferably, but not limited to, i) containing the measles vaccine together with a soluble substance in the skin forming microneedles, or ii) microneedles. piercing a needle and containing the measles vaccine within the puncture; and the like.

In the present invention, in order to impregnate the measles vaccine into the microneedles, the material forming the structure of the microneedles and the measles vaccine are filled and mixed in a mold for forming the microneedles, and then the mold is heated, dried, and separated to obtain microneedles. Needles can be made.

In the present invention, the soluble substance in the skin is, for example, hyaluronic acid (Hyaluronic acid), sodium carboxymethyl cellulose (Na-CMC, sodium carboxymethyl cellulose), vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol (Poly vinyl alcohol), and water-soluble polymers such as polyvinylpyrrolidone (Poly vinyl pyrrolidone); sugars such as xylose, sucrose, maltose, lactose, and trehalose; or mixtures thereof may be used.

When administering the measles vaccine using the microneedle according to the present invention, there is no risk of infection by the needle due to one-time use, and training for dose adjustment is unnecessary.

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the contents of the above-described invention, so the present invention is limited to those described in the drawings. should not be construed as limiting.
1 is a view showing one example of several methods for manufacturing microneedles according to the present invention.
Figure 2 shows a Franz diffusion cell for evaluating the drug release behavior of the microneedles according to the present invention.
Figure 3 is a graph showing the measles vaccine (Cam-Kovax) solution content in pig skin and acceptor solution.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Preparation of soluble microneedles>

Soluble microneedles are prepared by a solution casting method, and the solution is cast into a mold, filled with a liquid in a micromold by vacuum or centrifugal separation, and then dried.

As the material forming the microneedle structure, general synthetic and natural water-soluble polymers were used.

<Preparation of soluble microneedles containing measles vaccine components (Example 1)>

ingredient Example 1
(Unit: % by weight) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 HCO-40 0.2 Cam-Kovax solution 0.7 water To 100

After dissolving Oligo-HA (Hyaluronic acid), Na-CMC (Sodium carboxymethyl cellulose) and Trehalose in purified water, glycerin, PEG-40 hydrogenated castor oil (HCO-40) and measles vaccine Camco A microneedle solution was prepared by adding Cam-Kovax solution (prepared by dissolving with 0.7 mL of the attached solution). The prepared solution was cast in a silicon microneedle mold, and then centrifuged at 3000 rpm for 10 minutes to fill the micromold with the liquid. After filling the solution, it was dried in a drying oven (70° C.) for 3 hours, and the microneedles were separated from the silicon mold using an adhesive film (Example 1).

<Manufacture of measles vaccine component-containing patch (plane patch) (Comparative Example 1)>

ingredient Comparative Example 1
(Unit: % by weight) oligo-HA 6 Na-CMC 6 Trehalose 10 Glycerin 5 HCO-40 0.2 Cam-Kovax solution 0.7 water To 100

In order to compare the effect of the active ingredient impregnated into the microneedles and the active ingredient applied to the plane patch from which the microneedle shape was removed, a patch containing measles vaccine components was prepared with the composition shown in Table 2 above (Comparative Example 1).

<Experimental Example 1>

drug release behavior

The present inventors measured the Cam-Kovax solution content of porcine skin tissue and acceptor solution over time using a Franz diffusion cell using liquid chromatography.

Microneedles impregnated with Cam-Kovax solution were attached to pig skin, and the skin permeation amount of Cam-Kovax solution over time was compared.

As a result, as shown in FIG. 3, the plane patch containing the Cam-Kovax solution had an insignificant amount of about 50 μg or less permeated through the skin, but the Cam-Kovax solution impregnated into the microneedles Kovax) solution was directly penetrated into the skin by a needle, and the permeation amount was about 300 μg, showing about 6 times higher skin permeation amount.

Claims (8)

A water-soluble microneedle for skin penetration comprising a material for forming a microneedle and a measles vaccine,
The material forming the microneedle may be hyaluronic acid or a salt thereof; carboxymethyl cellulose or a salt thereof; trehalose; and glycerin,
Water-soluble microneedle, characterized in that when the microneedle is applied to the skin, the material forming the microneedle is dissolved by moisture in the skin. delete delete delete According to claim 1,
The measles vaccine is a water-soluble microneedle, characterized in that it contains 0.00001 to 1% by weight relative to the total weight of the microneedle. According to claim 1,
The microneedle is a water-soluble microneedle, characterized in that to improve the skin penetration of the measles vaccine. A microneedle patch comprising the water-soluble microneedle according to any one of claims 1, 5 and 6. A method for manufacturing a water-soluble microneedle according to claim 1,
S1) filling and mixing the measles vaccine and the material forming the microneedle in a mold; and
S2) The method of manufacturing a water-soluble microneedle comprising the step of heating and drying the mold and then separating the mold.

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