WO2015129545A1 - マイクロニードル・シート - Google Patents
マイクロニードル・シート Download PDFInfo
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- WO2015129545A1 WO2015129545A1 PCT/JP2015/054641 JP2015054641W WO2015129545A1 WO 2015129545 A1 WO2015129545 A1 WO 2015129545A1 JP 2015054641 W JP2015054641 W JP 2015054641W WO 2015129545 A1 WO2015129545 A1 WO 2015129545A1
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- Prior art keywords
- microneedle
- sheet
- skin
- microneedle sheet
- microneedles
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0061—Methods for using microneedles
Definitions
- One aspect of the present invention relates to a microneedle sheet used to assist administration of an active ingredient by a microneedle.
- a microneedle for administering an active ingredient through the skin and a device including the microneedle are known.
- a rotatable microstructure device described in the following Patent Document 1 includes a curved base material and a roller structure including a plurality of fine elements attached on the first surface of the base material. ing.
- the plurality of microelements have a predetermined size and shape so that when the microstructure device is placed on the skin and rolls in a predetermined direction, it penetrates the stratum corneum of the skin.
- the microneedle sheet according to one aspect of the present invention includes a plurality of microneedles formed on the sheet substantially along the main surface of the sheet, and the material of the microneedle is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol
- the microneedles are selected from graft copolymers of polyvinyl alcohol and polyethylene glycol, and the sheet is bent so that the microneedles rise from the main surface, and the raised microneedles pierce the skin.
- the microneedles made of a soluble material are substantially along the main surface of the sheet. This means that the tip of the microneedle does not protrude from the main surface until the microneedle is applied to the skin. Therefore, unless the microneedle sheet is applied to the skin, there is no concern that the microneedle will hit or get caught on another object. As a result, safety during handling of the microneedle can be ensured.
- the microneedle sheet made of the above-described soluble material has higher safety than the non-soluble material microneedle sheet, because physical irritation to the skin is reduced.
- FIG. 1 is a perspective view of an exemplary applicator.
- FIG. It is a figure which shows the usage method of the applicator shown in FIG. It is a figure which shows typically application of a microneedle sheet
- surface which shows the result of an Example. It is a graph which shows the result of the skin penetration test which is another Example. It is a graph which shows the result of said skin permeation test.
- the microneedle sheet 10 is a device for administering an arbitrary active ingredient (for example, a drug) into a living body, and has a large number of microneedles that pierce the skin.
- an arbitrary active ingredient for example, a drug
- the microneedle sheet 10 is strip-shaped and has a plurality of microneedles 12 formed on the sheet substantially along the main surface 11 of the sheet. These microneedles 12 are arranged so as to be aligned in the longitudinal direction and the width direction of the sheet, and the tips of all the microneedles 12 are directed to one end of the sheet (left direction in FIG. 1) without exception.
- the material of the microneedle sheet 10 and the microneedle 12 is not limited.
- the microneedle sheet 10 and the microneedle 12 may be made of any one of stainless steel, polyethylene terephthalate (PET), other metals, other resins, biodegradable materials, ceramics, or soluble materials. . Or you may produce the microneedle sheet
- the soluble material may be saccharide or non-saccharide.
- saccharide-soluble material examples include hydroxypropyl methylcellulose (HPMC) and hydroxypropylcellulose (HPC).
- non-saccharide-soluble material examples include polyvinyl alcohol (PVA) and polyvinyl alcohol / polyethylene glycol graft copolymer (graft copolymer of polyvinyl alcohol and polyethylene glycol).
- the material of the microneedle sheet 10 and the microneedle 12 may be selected from HPMC, HPC, PVA, or polyvinyl alcohol / polyethylene glycol / graft copolymer. For example, one of these four types may be selected. Good.
- the material of the microneedle sheet and the microneedle in the present specification is a substance intentionally used by the manufacturer for producing the microneedle sheet and the microneedle.
- substances that are not selected as materials for example, trace amounts of impurities
- the microneedle sheet and microneedle according to the present invention also include a microneedle sheet and a microneedle that finally contain a material not intended by the manufacturer in addition to the material intended by the manufacturer.
- the microneedle 12 can be formed by etching or laser. If the sheet is a metal, the microneedle 12 can be formed by dissolving the sheet with a chemical solution. If the sheet is a nonmetal, the microneedle 12 can be formed by evaporating the sheet with a laser. it can. In these cases, a gap is generated around the microneedle 12.
- the microneedles 12 may be formed by a technique other than etching and laser. As shown in FIG. 1, in this embodiment, the microneedle 12 has a triangular shape, but the shape of the microneedle is not limited at all. In any case, since it is not necessary to raise the microneedle 12 from the main surface 11 of the sheet in advance, the microneedle sheet 10 can be manufactured easily and inexpensively.
- the dimensions of the microneedle sheet 10 are not limited. Specifically, the lower limit of the thickness may be 5 ⁇ m or 20 ⁇ m, and the upper limit of the thickness may be 1000 ⁇ m or 300 ⁇ m.
- the microneedle sheet 10 is made of a soluble material, a thickness of 10 to 300 ⁇ m can be obtained by selecting one of HPMC, HPC, PVA, or polyvinyl alcohol / polyethylene glycol / graft copolymer as a material.
- seat 10 can be produced, the minimum and upper limit of the thickness in that case are not limited to this.
- the lower limit of the thickness of the microneedle sheet 10 when using any of these four kinds of soluble materials may be 20 ⁇ m, 30 ⁇ m, 40 ⁇ m, or 50 ⁇ m, and the upper limit of the thickness is 200 ⁇ m, 150 ⁇ m, 100 ⁇ m, 90 ⁇ m. 80 ⁇ m, 70 ⁇ m, 60 ⁇ m, or 50 ⁇ m.
- the lower limit of the thickness of the microneedle sheet 10 is determined in consideration of the strength of the microneedle 12 that punctures the skin, and the upper limit of the thickness is determined in consideration of the bendability of the sheet and the puncture characteristics of the microneedle 12. It is done.
- the lower limit of the length of the microneedle sheet 10 may be 0.1 cm or 1 cm, and the upper limit of the length may be 50 cm or 20 cm.
- the lower limit of the width of the microneedle sheet 10 may be 0.1 cm or 1 cm, and the upper limit of the width may be 60 cm or 30 cm.
- the lower limit of the length and width of the microneedle sheet 10 is determined in consideration of the dose of the active ingredient, and the upper limit of the length and width is determined in consideration of the size of the living body.
- the parameters related to the microneedle 12 are not limited. Specifically, the lower limit of the length of the microneedle 12 may be 10 ⁇ m or 100 ⁇ m, and the upper limit of the length may be 10000 ⁇ m or 1000 ⁇ m.
- the length of the microneedle 12 is a distance from the bottom of the microneedle 12 (the root portion rising from the main surface 11) to the top.
- the lower limit of the needle density may be 0.05 / cm 2 or 1 / cm 2
- the upper limit of the density may be 10,000 / cm 2 or 5000 / cm 2 .
- the lower limit of density is a value converted from the number and area of needles to which 1 mg of active ingredient can be administered
- the upper limit of density is a limit value in consideration of the shape of the needle.
- a method for preparing an active ingredient to be applied to the skin in the case of a microneedle sheet made of a soluble material, a method of enclosing the active ingredient in the microneedle sheet 10 itself, A method of coating the components, a method of applying the active ingredient on the skin before puncturing the microneedles 12 and a method of applying the active ingredient on the skin after puncturing the microneedles 12 It can be thought of as a technique. If the active ingredient is coated on the microneedle sheet 10 in advance, it is preferable to apply a coating solution having a predetermined viscosity to the entire sheet with a uniform thickness as much as possible, but the microneedle 12 is along the main surface 11. Such application can be easily performed. The coating may be performed using the principle of screen printing, or may be performed by other methods. When a biodegradable sheet is used, the active ingredient can be included in the sheet itself.
- the liner 20 is used to set the microneedle sheet 10 to the applicator 30 described later.
- the liner 20 is a belt-like sheet having a length and width larger than that of the microneedle sheet 10.
- the material of the liner 20 include plastics such as acrylic, but the material is not limited at all, and the liner 20 may be manufactured using, for example, metal or other types of resin.
- related figures show the liner 20 as being transparent or translucent, the liner 20 may be opaque.
- the microneedle sheet 10 is fixed to one end side of the liner 20 with a tape or an adhesive.
- the applicator 30 is a rectangular sheet-like instrument used when the microneedle sheet 10 is applied to the skin.
- the side on which the adhesive 34 described later is provided is defined as the lower side of the applicator 30, and the opposite side is defined as the upper side of the applicator 30.
- two slit-shaped through holes are formed along a direction orthogonal to the longitudinal direction (hereinafter referred to as “width direction”).
- One through hole is a hole for guiding the liner 20 and the microneedle sheet 10 from the upper side to the lower side of the main body 31, and is hereinafter referred to as a first through hole 32.
- the other through-hole is a hole for guiding the liner 20 peeled from the microneedle sheet 10 from the lower side to the upper side of the main body 31, and is hereinafter referred to as a second through-hole 33.
- the distance between the two through holes 32 and 33 may be determined in consideration of the application range of the microneedle sheet 10 to the skin, or may be determined in consideration of other criteria.
- An adhesive (adhesive layer) 34 is provided on the bottom surface of the main body 31 in a rectangular shape so as to surround the two through holes 32 and 33.
- the adhesive 34 has a role of fixing the applicator 30 on the skin.
- the range of the adhesive 34 is not limited.
- the adhesive 34 may be provided only along both edge portions along the longitudinal direction of the main body 31, or may be provided only along both edge portions along the width direction of the main body 31.
- the material of the main body 31 examples include plastics such as acrylic, but the material is not limited at all, and the main body 31 may be manufactured using, for example, metal or other types of resin.
- the main body 31 is shown as a transparent or translucent object, but the main body 31 may be opaque.
- the dimensions of the applicator 30 may be determined according to the dimensions of the microneedle sheet 10 or the liner 20.
- the width of the applicator 30 may be determined according to the width of the liner 20.
- the total length (length along the longitudinal direction) of the applicator 30 may be determined in consideration of the length of the microneedle sheet 10 or the application range of the microneedle sheet 10 to the skin.
- the user sets the liner 20 to which the microneedle sheet 10 is attached to the applicator 30. Specifically, the user passes one end of the liner 20 to which the microneedle sheet 10 is not fixed from the top to the bottom through the first through-hole 32 and the other end through the second through-hole 33. From above. With this preparation, the liner 20 is positioned on the bottom surface side of the applicator 30 between the two through holes 32 and 33 as shown in FIG.
- the user pulls one end of the microneedle sheet 10 from the first through-hole 32 to the bottom surface side of the applicator 30 and bends it so that the one end is positioned below the adhesive 34 and this state is maintained.
- Applicator 30 is applied to the application site of the active ingredient. By this series of operations, the applicator 30 is fixed on the skin S as shown in FIG.
- the microneedle sheet 10 is guided by the liner 20, passes through the first through-hole 32, and enters the space between the skin S and the bottom surface of the applicator 30.
- the microneedle sheet 10 is bent 180 degrees in this space. Then, as shown in FIG. 6 (or as shown enlarged in FIG. 8), the microneedle 12 located at the bent portion rises from the main surface 11 and the raised microneedle 12 pierces the skin S.
- the entire microneedle sheet 10 is applied to the skin as shown in FIG.
- the microneedle sheet 10 (sheet) is bent in the direction toward the tip of the microneedle 12. The microneedle 12 rises from the main surface 11 when the sheet is bent, and then pierces the skin.
- the user can peel the applicator 30 from the skin after this.
- the user may peel off the microneedle sheet 10 immediately or may continue to apply the microneedle sheet 10 to the skin S for a predetermined time.
- the microneedle sheet 10 is made of a soluble material, there is no need to bother removing the microneedle 12 from the skin.
- the microneedle sheet 10 is fixed to the liner 20 with a tape or an adhesive, but the tape or adhesive can also be used for fixing the microneedle sheet 10 on the skin. .
- microneedles 12 rising at a time between the applicator 30 and the skin S are one row along the width direction of the microneedle sheet 10. Naturally, the angle formed between the raised microneedle 12 and the main surface 11 is larger than 0 degree and smaller than 180 degrees.
- the puncture angle ⁇ (the angle formed between the microneedle 12 and the skin S) when the microneedle 12 rising from the main surface 11 pierces the skin is also greater than 0 degree and less than 180 degrees.
- the lower limit of the puncture angle may be 20 degrees, 34 degrees, or 40 degrees, and the upper limit of the angle may be 160 degrees, 140 degrees, or 100 degrees.
- the value r in FIG. 8 indicates the radius of curvature of the bent microneedle sheet 10.
- the maximum angle ⁇ formed by the microneedle 12 rising from the main surface 11 by the folding of the microneedle sheet 10 and the virtual line V extending from the center of curvature C to the root of the microneedle is greater than 90 degrees.
- the maximum angle may be in the range of 95 to 130 degrees, or may be in the range of 95 to 120 degrees.
- the ratio of the needle length h to the radius of curvature r is greater than 0.20, so that the microneedle 12 can be reliably pierced into the skin S.
- the microneedle sheet includes a plurality of microneedles formed on the sheet substantially along the main surface of the sheet, and the material of the microneedle is hydroxypropylmethylcellulose,
- the microneedles are selected from hydroxypropyl cellulose, polyvinyl alcohol, and graft copolymer of polyvinyl alcohol and polyethylene glycol, and the microneedles rise from the main surface when the sheet is bent, and the raised microneedles pierce the skin.
- the microneedle is substantially along the main surface of the sheet until the sheet is bent. This means that the tip of the microneedle does not protrude from the main surface until the microneedle is applied to the skin. Therefore, unless the microneedle sheet is applied to the skin, there is no concern that the microneedle will hit or get caught on another object. As a result, safety during handling of the microneedle can be ensured. For example, the user can safely store and transport the microneedle sheet and prepare it immediately before use.
- the microneedle material is a soluble material, there is no need to bother removing the microneedle from the skin. Furthermore, as compared with the microneedle sheet made of non-soluble material, the microneedle sheet made of soluble material as described above has high safety such as less physical irritation to the skin. In addition, a sustained drug absorption effect can be expected. Therefore, the convenience of the microneedle sheet is improved.
- the thickness of the sheet may be 10 to 300 ⁇ m.
- the microneedle sheet becomes thin and flexible, so that the sheet can be applied to the skin according to the shape of the living body, and as a result, the active ingredient can be efficiently administered. Can do.
- a microneedle sheet that is soluble in a living body and has a thinness that has not existed in the past can be produced.
- the puncture angle of the raised microneedle with respect to the skin may be 34 degrees or more and less than 180 degrees. In this case, the microneedle can be pierced into the skin more reliably.
- the maximum angle formed by the microneedle rising from the main surface and the imaginary line from the center of curvature of the sheet to the root of the microneedle may be larger than 90 degrees.
- the length of the portion of the microneedle that pierces the skin is increased, so that the skin permeability of the active ingredient is increased.
- the maximum angle may be 95 to 130 degrees. In this case, the length of the portion of the microneedle that pierces the skin is increased, so that the skin permeability of the active ingredient is increased.
- Microneedle sheets were prepared using various materials. Specifically, each material and water are weighed, mixed and stirred in a container to completely dissolve the material, and then defoamed by centrifuging the material at a rotational speed of 2000 rpm. A solution was made. The solution was coated on a liner (mold) so that the thickness after drying was 50 ⁇ m, and dried at 50 ° C. for 1 hour. A microneedle sheet was produced by subjecting the polymer film thus produced to laser processing. The length of each microneedle was 500 ⁇ m, and the density of the microneedles was 204 / cm 2 .
- trehalose maltose, hyaluronic acid, sodium chondroitin sulfate, dextrin, pullulan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), gelatin, polyacrylic acid, polyvinyl alcohol / polyethylene glycol / graft copolymer (Kollicoat) IR), polyvinyl alcohol (PVA), and two types of polyvinyl pyrrolidone (PVP (K30), PVP (K90)).
- a microneedle sheet can be satisfactorily produced. It was.
- a circle in the “Filmed” column indicates that a practical microneedle sheet (more specifically, a flat microneedle sheet) could be produced.
- the triangle mark indicates that although the sheet was produced, it was determined that it was not practical due to a reason such as bending. The cross mark indicates that the sheet could not be produced because the solution was repelled from the mold and became a lump.
- a puncture test was conducted on two types of microneedle sheets made of HPMC and PVA.
- a gel sheet was used as a skin model. Specifically, a cylindrical rod (diameter 0.8 to 1.2 mm; hereinafter referred to as a “cylindrical rod”) is arranged along the width direction of the microneedle sheet, and the microneedle sheet is placed with the cylindrical rod. The needle was raised by folding it, and the microneedle was stabbed into the gel sheet by moving the cylindrical bar along the upper surface of the gel sheet. In this test, the rising angle and puncture length were observed.
- the rising angle is the maximum value of the angle ⁇ shown in FIG.
- the puncture length is an average value of the lengths of the microneedles that have entered the gel sheet.
- the puncture length of each microneedle was obtained by subtracting the length of the exposed portion from the total length of the microneedle.
- microneedle sheet is punctured into human skin using a cylindrical rod having a diameter of 1 mm, and then the microneedle sheet is covered with a Teflon film, and the microneedle sheet is applied to human skin for 1 hour at 32 ° C. did. Thereafter, the microneedle sheet peeled from the human skin was observed with a microscope.
- microneedle sheets made of HPMC and two microneedle sheets made of PVA were made. Specifically, lidocaine hydrochloride, material (HPMC or PVA), and water are weighed, mixed and stirred in a container to completely dissolve the drug and material, and then the aqueous solution is centrifuged to degas Thus, a coating solution was prepared. The solution was coated on a liner (mold) so that the thickness after drying was 50 ⁇ m, and dried by heating. A microneedle sheet was produced by subjecting the polymer film thus produced to laser processing. Both of the two microneedle sheets made of HPMC contained about 25.8% by weight lidocaine hydrochloride after completion.
- Both of the two microneedle sheets made of PVA contained about 8.6% by weight lidocaine hydrochloride after completion.
- the area of each microneedle sheet was 1.5 cm 2 .
- the length of each microneedle was 500 ⁇ m, and the density of the microneedles was about 200 / cm 2 .
- Each of the four produced microneedle sheets was subjected to a skin permeation test using a Franz diffusion cell. Specifically, after applying the microneedle sheet to the stratum corneum side of a human skin piece having an area of 5 cm 2 , the skin piece is attached to a Franz diffusion cell so that the dermis side faces the receptor tank, The cell was kept at 32 ° C.
- “application of the microneedle sheet (to the skin piece)” in this test means to include two types of application methods.
- One is a method in which the microneedle sheet is placed on the skin piece without puncturing the individual microneedle into the skin piece, and the other is a method in which the individual microneedle is punctured into the skin piece.
- the microneedle was not punctured into the skin piece, and for the other, the microneedle was punctured into the skin piece.
- the microneedle sheets made of PVA the microneedle was not punctured on the skin piece on the one hand, and the microneedle was pierced on the skin piece on the other hand.
- the phosphate buffered saline is replaced at a constant rate in the receptor tank of this cell, and the solution in the receptor tank is sampled every predetermined time.
- the concentration of lidocaine hydrochloride was measured by high performance liquid chromatography. The measurement was performed until 24 hours passed from the start. The amount of drug permeation at each time was determined from the measured values, and the skin permeation rate ( ⁇ g / cm 2 / h) and the cumulative permeation amount ( ⁇ g / cm 2 ) at each time were further determined. In addition, two types of utilization (%) were obtained.
- the first utilization rate (%) is the ratio of the cumulative permeation amount after 24 hours to the amount of drug (lidocaine hydrochloride) initially contained in the microneedle sheet (hereinafter referred to as “initial amount”).
- the second utilization rate (%) is obtained by the following equation group using the value of the remaining rate.
- the second utilization rate since the drug remaining in the skin piece without reaching the receptor tank is also counted as the utilization rate, the second utilization rate tends to be higher than the first utilization rate.
- the two types of utilization rates were obtained only when the microneedle was punctured into the skin piece.
- the test results are shown in Table 1 below.
- the “Material” column indicates the substance used as the material of the microneedle sheet.
- the “application” column indicates whether the microneedle has been punctured into the skin piece.
- the maximum skin permeation rate (Jmax) is the maximum value among a plurality of skin permeation rates in each microneedle sheet.
- FIG. 10 shows a graph (a) of the cumulative permeation amount and a graph (b) of the skin permeation rate for the HPMC microneedle sheet.
- rate are shown in FIG.
- the vertical axis and the horizontal axis of graph (a) are the accumulated transmission amount and the elapsed time (h) from the start of measurement, respectively.
- the vertical axis and horizontal axis of the graph (b) are the skin permeation rate and the elapsed time (h) from the start of measurement, respectively.
- a microneedle sheet made of HPMC and a microneedle sheet made of PVA were prepared according to the method described in the above item “[Production of microneedle sheet]”. Moreover, the microneedle sheet
- SUS stainless steel
- the skin reaction was evaluated according to the Draize method. Specifically, the microneedle sheet was applied to the shaved back of the rabbit, and the microneedle sheet was fixed to the skin using an adhesive tape. At this time, the individual microneedles were punctured into the skin. The microneedle sheet is removed 24 hours after its application, and erythema and edema formation is visually observed at 2, 24, and 48 hours after removal, based on the evaluation criteria of Draize (Table 2) Scoring. In these series of observations, six rabbits were used for each type of microneedle sheet. Further, the primary irritation index (PI) was calculated, and the skin primary irritation was determined by using the following Draize evaluation criteria (Table 3).
- PI primary irritation index
- the primary stimulation index is calculated as follows. First, an average score of 6 samples was determined for each of erythema and edema formation at 2 hours, 24 hours, and 48 hours after removal of the microneedle sheet. Then, the total of the average score was calculated
- the evaluation results are shown in Table 4 below.
- the “Material” column indicates the substance used as the material of the microneedle sheet.
- the symbol “#” in the table indicates that punctate bleeding or punctate bleeding marks were observed, the symbol “+” indicates that erythema or wrinkles at the edge was observed, and the symbol “$” Indicates that scale was observed.
- the lower part of the score column is the total average score in each group.
- the shape and structure of the applicator are not limited as long as the microneedle 12 can be raised by bending the microneedle sheet 10.
- the applicator may be shaped like a straight single bar.
- the applicator may comprise any mechanical, electrical, or electronic structure or control means. Whether or not the liner 20 is used may be arbitrarily determined in connection with the fact that the aspect of the applicator is not limited.
- the shape of the microneedle sheet is not limited to a belt shape, and may be, for example, a rectangle having substantially the same length and width, or a circle or an ellipse. Depending on the shape of the microneedle sheet, the applicator may not be used.
- microneedle sheet according to the present invention can be used in combination with other percutaneous absorption promotion techniques such as electricity (iontophoresis), pressure, magnetic field, ultrasound (sonophoresis) and the like. .
- electricity iontophoresis
- pressure iontophoresis
- magnetic field iontophoresis
- ultrasound sonophoresis
- the combined use of the microneedle sheet and other techniques such as these can further increase the amount of drug absorption.
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Abstract
Description
各種の材料を用いてマイクロニードル・シートを作製した。具体的には、各材料及び水を秤量し、容器中で混合および攪拌して材料を完全に溶解させた後、その材料を2000rpmの回転速度で遠心させることで脱泡し、これにより塗工溶液を作製した。その溶液を、乾燥後の厚さが50μmになるようにライナー(型)上に塗工し、50℃で1時間乾燥させた。このように作製したポリマーフィルムにレーザー加工を施すことでマイクロニードル・シートを作製した。個々のマイクロニードルの長さは500μmとし、マイクロニードルの密度は204本/cm2とした。
続いて、良好に作製できた4種類のマイクロニードル・シートのうち、HPMCおよびPVAを材料とする2種類のマイクロニードル・シートについてマンドレル試験を実施して、耐屈曲性を評価した。屈曲試験機には、株式会社井元製作所のIMC-A0F0型を採用した。具体的には、マイクロニードル・シートの中心に屈曲試験機のマンドレル(径1mm)をセットし、試験機ごとマイクロニードル・シートを折り曲げた。そして、折り曲げたマイクロニードル・シートを顕微鏡で観察することにより、割れ、亀裂、または破断があるか否かを評価した。
HPMCおよびPVAを材料とする2種類のマイクロニードル・シートについて穿刺試験を行った。皮膚のモデルとしてゲルシートを用いた。具体的には、円柱状の棒(径0.8~1.2mm。以下では「円柱棒」という)をマイクロニードル・シートの幅方向に沿って配置し、その円柱棒でマイクロニードル・シートを折り返すことでニードルを立ち上げ、その円柱棒をゲルシートの上面に沿って動かすことでマイクロニードルをゲルシートに刺した。この試験では、立ち上がり角度および穿刺長さを観察した。ここで、立ち上がり角度とは、図8に示す角度φの最大値である。
HPMCおよびPVAを材料とする2種類のマイクロニードル・シートについて、ヒト皮膚を用いてマイクロニードルの溶解性能を評価した。まず、径1mmの円柱棒を用いてマイクロニードル・シートをヒト皮膚へ穿刺し、その後、マイクロニードル・シートをテフロンフィルムで覆い、32℃の条件下で1時間マイクロニードル・シートをヒト皮膚に適用した。その後、ヒト皮膚から剥離したマイクロニードル・シートを顕微鏡で観察した。
塩酸リドカインを含有させた、HPMC製またはPVA製のマイクロニードル・シートを用いて、ヒト皮膚に対する塩酸リドカインの透過試験を行い、この薬物が投与される量を評価した。
第2の利用率(%)=100-残存率
残存率(%)={(24時間経過後のマイクロニードル・シートに残存する薬物量)+(皮膚片の表面に付着した薬物量)}/(当初量)×100
第2の利用率では、レセプタ槽まで到達せずに皮膚片内に残る薬物も利用率にカウントされるので、第2の利用率は第1の利用率より高くなる傾向がある。2種類の利用率は、マイクロニードルを皮膚片に穿刺させた場合でのみ求めた。
上記の項目“[マイクロニードル・シートの作製]”で説明した方法に従って、HPMC製のマイクロニードル・シートおよびPVA製のマイクロニードル・シートを用意した。また、マイクロニードルの長さおよび密度がHPMC製およびPVA製のマイクロニードル・シートと同じである、ステンレス鋼(SUS)製のマイクロニードル・シートを比較例として用意した。
Claims (5)
- シートの主面に略沿って該シートに形成された複数のマイクロニードルを備え、
前記マイクロニードルの材料が、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、および、ポリビニルアルコールとポリエチレングリコールとのグラフトコポリマーの中から選択され、
前記シートが曲げられることで前記マイクロニードルが前記主面から立ち上がり、立ち上がった該マイクロニードルが皮膚に刺さる、
マイクロニードル・シート。 - 前記シートの厚さが10~300μmである、
請求項1に記載のマイクロニードル・シート。 - 前記立ち上がったマイクロニードルの前記皮膚に対する穿刺角度が34度以上且つ180度未満である、
請求項1または2に記載のマイクロニードル・シート。 - 前記主面から立ち上がった前記マイクロニードルと、前記シートの曲率中心から該マイクロニードルの根元に至る仮想線との成す最大角度が90度より大きい、
請求項1~3のいずれか一項に記載のマイクロニードル・シート。 - 前記最大角度が95~130度である、
請求項4に記載のマイクロニードル・シート。
Priority Applications (5)
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JP2016505166A JP6325082B2 (ja) | 2014-02-27 | 2015-02-19 | マイクロニードル・シート |
EP15755798.4A EP3111987B1 (en) | 2014-02-27 | 2015-02-19 | Microneedle sheet |
KR1020167023955A KR102135495B1 (ko) | 2014-02-27 | 2015-02-19 | 마이크로 니들·시트 |
US15/119,983 US20170049695A1 (en) | 2014-02-27 | 2015-02-19 | Microneedle sheet |
CN201580010336.9A CN106061544B (zh) | 2014-02-27 | 2015-02-19 | 微型针薄片 |
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PCT/JP2015/054641 WO2015129545A1 (ja) | 2014-02-27 | 2015-02-19 | マイクロニードル・シート |
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US (1) | US20170049695A1 (ja) |
EP (1) | EP3111987B1 (ja) |
JP (1) | JP6325082B2 (ja) |
KR (1) | KR102135495B1 (ja) |
CN (1) | CN106061544B (ja) |
TW (1) | TWI630006B (ja) |
WO (1) | WO2015129545A1 (ja) |
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JPWO2017145891A1 (ja) * | 2016-02-24 | 2018-09-06 | 久光製薬株式会社 | アプリケータ |
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JP2020099513A (ja) * | 2018-12-21 | 2020-07-02 | ロレアル | マイクロニードルシートを使用するキット及び美容方法 |
CN114555065A (zh) * | 2019-10-08 | 2022-05-27 | 久光制药株式会社 | 微针片材以及敷贴器 |
CN114980953A (zh) * | 2020-04-06 | 2022-08-30 | 株式会社医隆 | 装有诱导化妆品吸收用微型针头的化妆品注射器及其制作方法 |
CN116585606A (zh) * | 2023-06-15 | 2023-08-15 | 徕兄健康科技(威海)有限责任公司 | 一种可自调节的局部麻醉用微针贴片 |
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Also Published As
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JPWO2015129545A1 (ja) | 2017-03-30 |
JP6325082B2 (ja) | 2018-05-16 |
KR20160125405A (ko) | 2016-10-31 |
CN106061544A (zh) | 2016-10-26 |
KR102135495B1 (ko) | 2020-07-17 |
US20170049695A1 (en) | 2017-02-23 |
EP3111987A4 (en) | 2017-10-11 |
EP3111987B1 (en) | 2022-04-20 |
CN106061544B (zh) | 2019-11-26 |
TW201545781A (zh) | 2015-12-16 |
EP3111987A1 (en) | 2017-01-04 |
TWI630006B (zh) | 2018-07-21 |
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