WO2020138482A1 - Microneedle array for bcg vaccine - Google Patents

Abstract

Because the needle tips do not come out of the tube in a conventional BCG vaccine tube needle, strength and technique were necessary and it was difficult to easily, evenly and reliably insert needles and perform a vaccination, which resulted in the problems that it was not possible to achieve the sufficient number of needle marks that shows the inoculation effect and that the child being vaccinated experienced pain and distress.　These problems are solved by adopting a microneedle patch case of a thermoplastic plastic as the BCG vaccination tube needle, and setting the needle length to 0.2-1.0 mm.

Description

Microneedle array for BCG inoculation

The present invention relates to a transdermal vaccine inoculation technique, and more particularly to a BCG vaccine administration technique.

To use the BCG inoculation needle, hold the needle and apply the inoculum to the skin evenly on the wing. Then, squeeze the tube so that the opposite side of the needle touches the palm of the hand, and inoculate the needle against the skin of the inoculated child by pressing strongly against the skin until the pterygium contacts the skin.

The BCG inoculation tube needle has the same length as the tube and does not protrude from the tube, so strong pressure is required to insert the needle into the skin during inoculation. 2. Because strong force is required, the inoculated child will experience more pain in pressing the tube strongly than slight pain in the needle. 3. Since the force is required, the force is not evenly applied to the 9 needles, and the inoculation is likely to be uneven, resulting in a technical difference in the inoculation. 4. Because it requires a strong force, the doctor will hurt the palm with the needle. Some doctors use protective methods such as boards and cloths on their hands. 5. Because the inoculum must be evenly applied to the skin beforehand, it may flow over the skin.

In order to reduce the defects of the BCG inoculation tube needle, the technology of a BCG inoculation tube needle with a longer needle tip has been published (Patent Document 1). 

JP-A-2003-144545

The conventional BCG inoculation tube needle requires force and technology because the needle tip does not come out of the tube, and it is difficult to evenly and reliably inject the needle to inoculate it. There was a problem in that the number could not be obtained, and the inoculated child had great pain and pain.

In order to solve the above-mentioned problems, the present inventors have conducted extensive studies to apply the characteristics of a microneedle array, which is promising as a percutaneous absorption preparation, to a BCG inoculation tube needle, and have completed the present invention.
The present invention is as described below.
[1] A microneedle array in which the needle length of the microneedle is 0.2 to 1.0 mm, the needle density is 20 to 400 needles/cm ² , and the area of the substrate is 0.6 to 2.0 cm ^2. A needle for transdermal vaccination, comprising:
[2] The needle according to [1], wherein the needle density is smaller in the central portion of the substrate than in the peripheral portion of the substrate.
[3] The needle according to [1] or [2], wherein the transdermal vaccine is a BCG vaccine.
[4] The needle according to [3], wherein the transdermal vaccine is a BCG vaccine and the needle volume when inserted into the skin is 0.2 mm ³ or more.
[5] The base of the microneedle is selected from the group consisting of polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid and mixtures thereof, [1] to [4] Needle.
[6] A microneedle array in which the needle length of the microneedle is 0.2 to 1.0 mm, the needle density is 20 to 400 needles/cm ² , and the area of the substrate is 0.6 to 2.0 cm ^2. And a support film, wherein the support film is larger than the area of the substrate of the microneedle, and the microneedle patch in which the microneedle array is adhesively fixed to one surface of the support film, and
It consists of a circular microneedle patch case made of thermoplastic polymer,
The support film is made of a material that can be heat-sealed with the thermoplastic polymer,
The patch case holds the microneedle array in a ring by heat-sealing with the support film,
A tube needle for transdermal vaccination, wherein the width of the skin contact surface of the patch case is 2 mm or more.
[7] The tube needle according to [6], wherein the needle density is smaller in the central portion of the substrate than in the peripheral portion of the substrate.
[8] The tube needle according to [6] or [7], wherein the transdermal vaccine is a BCG vaccine.
[9] The tubular needle according to any one of [6] to [8], wherein the distance from the support film to the skin contact surface is 1 mm or more.
[10] The microneedle base is selected from the group consisting of polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid, and mixtures thereof, in any one of [6] to [9]. Tube needle.
[11] The tubular needle according to any of [6] to [10], wherein the material for the support film is a thermoplastic polymer film or a nonwoven fabric.
[12] A tube needle for percutaneous vaccination for inoculating a microneedle array set in an applicator with an appropriate amount of percutaneous vaccine.
[13] The tube needle according to [12], wherein the transdermal vaccine is a BCG vaccine.

By inserting the percutaneous vaccination tube needle of the present invention into the skin by using a general microneedle patch applicator, it is possible to perform vaccination by simply bringing the patch case into light contact with the skin. Does not require power. 2. The inoculated child does not have to feel the pain of pressing the needle strongly with only slight pain of the needle. 3. The doctor can inoculate the palm of the tube without hurting the palm, and is free from heavy labor. 4. Can be inoculated evenly and accurately. 5, the difference in inoculation technology will disappear.

FIG. 1 is a diagram showing an embodiment of a microneedle patch case usable in the present invention. FIG. 2 is a plan view showing an embodiment of a BCG vaccination tube needle and a patch holder. FIG. 3 is a diagram showing a state before attachment of the BCG vaccination tube needle and the applicator. FIG. 4 shows one embodiment of a BCG vaccination tube needle attached to an applicator. FIG. 5 is a photograph of a conventional BCG tube needle. FIG. 6 is a diagram showing an outline of a test using a parafilm laminate as a skin model.

Percutaneous Vaccination Needle The percutaneous vaccination needle of the present invention comprises a particular microneedle array. The BCG vaccine corresponds to the transdermal vaccine, but any inoculation method in which the surface of the skin is scratched with a needle or the like and the vaccine is absorbed from the scratch can be used without being limited to BCG.

The needle length of the microneedle used in the needle for transdermal vaccination of the present invention is 0.2 to 1.0 mm, and may be 0.4 to 1.0 mm. The needle density is 20 to 400 needles/cm ² . Although the microneedles stand on the substrate, the density thereof may be uniform over the entire surface of the substrate, or may be sparse in the central portion of the substrate and dense in the peripheral portion. Further, donut-shaped needles may be present in which the microneedles do not exist in the central portion of the substrate.
When the surface of the substrate is circular, the central part of the substrate is inside the circumference of 8/10 to 3/10 of the radius from the center of the circle, and the peripheral part of the substrate is outside the central part. It is preferable. In the case of an ellipse, it is set according to a circle.
When the surface of the substrate is a quadrangle, the central portion of the substrate is inside the four sides connecting the four points from the center of the quadrangle to the points 8/10 to 3/10 of the diagonal line, and the peripheral portion of the substrate is the central portion. It is preferably outside the part. In the case of triangles and polygons of pentagons or more, they are set according to quadrangles.
The microneedles form a microneedle array together with the substrate, and the area of the substrate is 0.6 to 2.0 cm ² . The shape of the substrate is usually circular or rectangular.
The needle length is preferably 0.5 to 0.8 mm. The needle length may be uniform, or may be high in the central portion and low in the peripheral portion. For example, the configuration may be 0.8 mm at the central portion and 0.6 mm at the peripheral portion. The needle density is preferably 40 to 200 needles/cm ² . The area of the substrate is preferably 0.8 to 1.5 cm ² .
The diameter of the apex of the needle tip is about 20 μm or more and about 50 μm or less. The needle is inserted from the surface of the skin, and it is preferable that the volume of the skin is 0.2 mm ³ or more on the assumption that the volume of the needle inside the skin at the time of insertion remains within the skin (depth is within 200 μm).

As a base for the microneedles, basically, a material that can be used for conventional microneedles can be used, but a thermoplastic polymer is preferable from the viewpoint of mass production possibility, and further biosafety is ensured. Materials are preferred. Examples thereof include polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid, polyethylene terephthalate, nylon, polycarbonate, COP (cyclic olefin polymer) and mixtures thereof, and more preferred are polylactic acid and poly(lactic acid). -Glycolic acid) copolymers, polyglycolic acid and mixtures thereof.
Alternatively, the base of the microneedle is hyaluronic acid, dextran, polyvinylpyrrolidone, sodium chondroitin sulfate, hydroxypropylcellulose, polyvinyl, as long as it has the property of not being completely dissolved for at least 15 minutes after being molded into microneedles and piercing the skin. It may be alcohol or a mixture thereof.

The needle for transdermal vaccination of the present invention comprises the above microneedle array. From the viewpoint of ease of handling, an adhesive tape may be attached to the back surface of the microneedle array, that is, a microneedle patch. The microneedle patch may be a backside adhesive tape to which a support film is further adhered. The support film will be described later.

Method for manufacturing needle for transdermal vaccination The needle for transdermal vaccination can be manufactured using a mold (mold). Although press molding and injection molding are possible, injection molding is preferable from the viewpoint of mass molding. A needle for percutaneous vaccination based on an injection-moldable thermoplastic polymer may be manufactured by injection-molding the base using a mold (for example, Japanese Patent Laid-Open No. 2003-238347, [0017]. , [0018]). As the injection molding die, stainless steel, heat resistant steel, superalloy, or the like can be used. A typical mold has notches corresponding to 20 to 400 microneedles per square cm to create the shape of microneedles. A fine processing means such as a grinder can be used to make the cut portion.

Percutaneous Vaccination Tube Needle The percutaneous vaccination tube needle of the present invention comprises a microneedle patch and a microneedle patch case.

1) Microneedle patch The microneedle array includes the microneedle array, that is, the transdermal vaccination needle of the present invention, and a support film. The support film supports the microneedle array and is larger than the substrate area of the microneedle. The microneedle array is adhesively fixed to one side of the support film. Adhesion between the microneedle array and the support film can be performed via an adhesive or an adhesive tape.
In the present specification, when the microneedle array is adhesively fixed to the support film, the surface is defined as the surface of the support film and the opposite surface is defined as the back surface. In the present invention, the peripheral portion of the back surface of the support is heat-sealed to the patch case.

2) Microneedle patch case The microneedle patch case is made of thermoplastic polymer. As the thermoplastic polymer, a polyolefin resin, polyvinyl chloride, polycarbonate, nylon resin, polyethylene terephthalate (PET) or the like can be used, but a polyolefin resin is preferable for one having a low heat molding temperature because molding is easy. Specifically, polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer and the like are preferable.
Since the microneedle patch case accommodates and holds the microneedle patch in the case, the accommodating portion is larger than the area (0.6 to 2.0 cm ² ) of the substrate of the microneedle and can accommodate the substrate of the microneedle. The shape. Typically, the microneedle patch case is annular as shown in FIG.

3) Thermal fusion of microneedle patch and microneedle patch case The support film thermally fused to the microneedle patch case is located at a predetermined distance from the skin contact surface. The distance from the support film to the skin adhesive surface is 2 mm or more, preferably 2 mm or more and 20 mm or less. The distance between the support film and the skin adhesive surface is indicated by the distance B in FIG. 1, and it is possible to reliably puncture the skin with the microneedles by adjusting this distance appropriately.

The support film is made of a material that can be heat-sealed with the thermoplastic polymer that is the material of the microneedle patch case. A thermoplastic resin or a non-woven fabric is preferable, but the same material as the support film and the material of the patch case are desirable because the heat fusion is easy when the same type of resin is used. Specifically, the support film is, like the case, a polyolefin resin (polyethylene: melting point 140°C, polypropylene: melting point 180°C), polyvinyl chloride (melting point 280°C), nylon resin (melting point largely depends on the composition. , Polyethylene terephthalate (PET) (melting point: 270° C.), and the like. The support film and the support non-woven fabric may use a single thermoplastic resin, but may be a laminate film which is a resin having different heat-sealing surfaces and adhesive surfaces. When the support film is a laminate film and the patch case is made of polyolefin, the back side of the support film is fused to the patch case, so the melting point in the support film is relatively low (preferably the melting point is 200°C or less. ), for example, polyolefins such as polyethylene and polypropylene are preferable, and the surface of the support film is preferably a thermoplastic polymer having a high melting point (preferably having a melting point of 200° C. or higher), for example, polyethylene terephthalate.
In this case, the heat fusion property is more suitable for the polyolefin, and it is clear that polyethylene terephthalate is more preferable than the polyolefin for applying the pressure-sensitive adhesive and holding it stably, due to the difference in polarities of the two polymers.

No special method is required for heat-sealing the microneedle patch and the patch case, and the tip of the sharp metal rod may be heated above the melting point of the thermoplastic polymer and pressed against the heat-sealing portion. Regarding heat fusion to the melting point of the thermoplastic polymer or higher, heat fusion by high frequency heating, heat fusion by laser heating, and the like are also possible.

As shown in FIG. 2, the microneedle patch case holds the microneedle patch inside the ring by heat fusion with the support film.

In the thus manufactured tube needle for transdermal vaccination, the ring of the microneedle patch case serves as the skin contact surface, and its width is 2 mm or more. More preferably, it is 3 mm or more and 10 mm or less.

Explaining an example of the embodiment of the present invention, the structure of a BCG vaccination needle is composed of 40 to 200 needles/cm ² needle and a patch supporting the needle as shown in FIG. The patch diameter is 1 cm. The BCG vaccination needle is held in the patch case by the protective adhesive tape on the back surface, and becomes the BCG vaccination tube needle of the present invention. In FIG. 3, the microneedle patch is held by the protective adhesive tape in the central portion of the patch case.

The above-mentioned needle for transdermal vaccination may be further stored in a holder. The holder can protect the microneedles during transportation and storage. The material of the holder may be the same as that of the patch case body, but a polyolefin resin is desirable for a material having a low heat molding temperature because molding is easy. Specifically, polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer and the like are preferable. One embodiment of the holder is shown in FIG.

The needle for transdermal vaccination is sterilized and packaged as it is or in the holder.

Dermal needles for vaccination should be taken out from the sterile packaging and used in the microneedle patch applicator at the clinical site of vaccination. An example of a microneedle applicator equipped with a BCG vaccination tube needle is shown in FIG. The microneedle applicator suitable for transdermal vaccination is preferably driven by the impact force of a spring, an example of which is shown in FIG. The microneedle applicator of FIG. 3 is composed of an applicator piston portion 6 and an applicator holding portion 7. In FIG. 4, the applicator piston portion 6 has a BCG vaccination tube needle 5 attached to its tip. ..

In FIG. 4, the BCG vaccination needle is inserted into the skin by the compression/release mechanism of the spring in the applicator holding part 7. The inoculator (doctor) holds the applicator holding part 7 with one hand and vertically presses the tip of the ring of the BCG vaccination tube needle 5 against the skin to which the BCG drug solution is applied to push the applicator holding part 7. Then, the spring is compressed and locked by the latch. By unlocking the latch with a trigger or the like, the applicator piston part 6 pushes the microneedle patch from the back side by the impact force of the spring, peeling off the fusion between the support film and the patch case, and the BCG vaccination needle ( Microneedles) reach inside the skin. The impact force of the applicator is set so that the spring constant is optimized so that it is suitable for infants and children, and that it does not cause excessive pain. By this operation, the BCG drug solution is inoculated into the skin, but according to the present invention, a strong force is not required, and the inoculation can be performed easily, surely, and evenly inoculating.

The BCG vaccine is applied to the skin in advance, but an appropriate amount may be included in the microneedle array set in the applicator. The microneedle array, which is a BCG vaccination needle, may be immediately removed after being inserted into the skin, or the microneedle may be retained in the skin for a suitable time with a protective adhesive tape and then removed. The number of inoculations is usually 2, and inoculate so that the circular marks on the patch case touch each other. When immunization against tuberculosis is induced by one inoculation, the number of one inoculation may be sufficient.

Examples of the present invention are shown below, but the present invention is not limited to the examples.

Example 1
BCG vaccination tube needle A microneedle array formed by injection-molding a needle having a needle length of 400 μm and made of 110 polyglycolic acid on a disk-shaped substrate having a diameter of 10 mm is used as a protective adhesive tape (adhesive is HiPAS( Acrylic type) adhesive, made by Cosmedy Pharmaceutical Co., Ltd.), and the support sheet on the back side of the protective adhesive tape is fused and fixed to the patch case shown in FIG. 1 to form a BCG vaccination tube needle. Manufactured.
The manufactured BCG vaccination tube needle was fixed to the applicator shown in FIG. The applicator was a spring type, the spring constant was 0.427 N/mm, and the compression length was 40 mm.

Comparative Example 1
Conventional BCG tube needle Nine thin needles are fixed in a plastic cylinder with a diameter of 2 cm at intervals of 4.5 mm, and the needle tip is almost at the same height as the edge of the cylinder. The photograph is shown in FIG.

Test Using Parafilm Laminate as Skin Model A model experiment was conducted in order to discuss the depth of insertion of the inoculation needle into the skin depending on the strength of the pressing force. As a sample, the BCG inoculation tube needle of Comparative Example 1 and the BCG vaccination tube needle of Example 1 (having a microneedle array manufactured by Cosmedy Pharmaceutical Co., Ltd.) were used. As a model skin, a laminate (8 sheets) of parafilm (thickness: 130 μm) was used. Parafilm can be used as a skin model according to the following reference (9).
(9) E. Larranneta, et al., A proposed model membrane and test method for microneedle insertion studies, Int. J. Pharmaceutics, 472,65-73 (2014).

The BCG vaccination tube needle of Example 1 was set in an applicator, pressed against the parafilm laminate, and shock-administered (FIG. 6). In the parafilm laminate after administration, the number of puncture marks from the top was observed and used as the puncture depth. If only the first sheet is inserted, the insertion is determined to be 130 μm, the second sheet up to 260 μm, and the third sheet is inserted up to 390 μm. The administration was performed 3 times, and the penetration depth was 390 μm in each case. It was found that a stable compressive force was always obtained by using the applicator, and the penetration depth became stable depending on the microneedle length.

Separately, a BCG inoculation tube needle is installed by using a tensile compression tester manufactured by Shimadzu Corporation in the same manner as in FIG. 6, and the pressing force is changed to be inserted into the model skin (parafilm/thickness=130 μm). The depth was measured.
Table 1 shows the compression strength and the needle penetration depth.

From Table 1, it is clear that as a result of the behavior of inserting into the parafilm by pressing the BCG inoculation tube needle, the skin penetration depth increases as the pressing force increases. In order to keep the needle in the skin when inoculating a newborn baby, it is necessary to set the penetration depth to 1,000 μm or less, and it is understandable that a doctor's technique is necessary for applying the inoculation tube needle to the skin.
Skin administration of microneedles using an applicator leads to a new BCG inoculation method that is not dependent on skill, and both doctors and newborns can benefit from it.

1 Microneedle patch 2 Protective adhesive tape 3 Patch case 4 Holder 5 BCG vaccination tube needle 6 Applicator piston part 7 Applicator holding part

Claims (13)

1. The microneedle includes a microneedle array having a needle length of 0.2 to 1.0 mm, a needle density of 20 to 400 needles/cm ² , and a substrate area of 0.6 to 2.0 cm ² . Needle for transdermal vaccination.
2. The needle according to claim 1, wherein the needle density is smaller in the central portion of the substrate than in the peripheral portion of the substrate.
3. The needle according to claim 1 or 2, wherein the transdermal vaccine is a BCG vaccine.
4. The needle according to claim 3, wherein the transdermal vaccine is a BCG vaccine, and the needle volume when inserted into the skin is 0.2 mm ³ or more.
5. The needle according to any one of claims 1 to 4, wherein the base of the microneedle is selected from the group consisting of polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid and a mixture thereof.
6. Microneedle array having a needle length of 0.2 to 1.0 mm, a needle density of 20 to 400 needles/cm ² , and a substrate area of 0.6 to 2.0 cm ² , and a support. A microneedle patch including a film, wherein the support film is larger than the area of the substrate of the microneedle, and the microneedle array is adhesively fixed to one surface of the support film; and
   It consists of a circular microneedle patch case made of thermoplastic polymer,
   The support film is made of a material that can be heat-sealed with the thermoplastic polymer,
   The patch case holds the microneedle array in a ring by heat-sealing with the support film,
   A tube needle for transdermal vaccination, wherein the width of the skin contact surface of the patch case is 2 mm or more.
7. The tube needle according to claim 6, wherein the needle density is smaller in a central portion of the substrate than in a peripheral portion of the substrate.
8. The tube needle according to claim 6 or 7, wherein the transdermal vaccine is a BCG vaccine.
9. The tube needle according to any one of claims 6 to 8, wherein the distance from the support film to the skin contact surface is 1 mm or more.
10. The needle according to any one of claims 6 to 9, wherein the base of the microneedle is selected from the group consisting of polylactic acid, poly(lactic acid-glycolic acid) copolymer, polyglycolic acid and mixtures thereof. ..
11. The tube needle according to any one of claims 6 to 10, wherein the material of the support film is a thermoplastic polymer film or a non-woven fabric.
12. A percutaneous vaccination tube needle for inoculating the microneedle array set in the applicator with an appropriate amount of percutaneous vaccine.
13. The tube needle according to claim 12, wherein the transdermal vaccine is a BCG vaccine.

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