U.S. patent application number 16/668066 was filed with the patent office on 2020-02-27 for microneedle device.
The applicant listed for this patent is HISAMITSU PHARMACEUTICAL CO., INC.. Invention is credited to Shinpei NISHIMURA, Seiji TOKUMOTO.
Application Number | 20200061359 16/668066 |
Document ID | / |
Family ID | 55459162 |
Filed Date | 2020-02-27 |
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United States Patent
Application |
20200061359 |
Kind Code |
A1 |
NISHIMURA; Shinpei ; et
al. |
February 27, 2020 |
Microneedle Device
Abstract
The present invention provides a microneedle device comprising:
a substrate; a microneedle disposed on the substrate; and a coating
layer formed on the microneedle; wherein the coating layer
comprises a physiologically active substance, arginine, and
glycerin.
Inventors: |
NISHIMURA; Shinpei;
(Tsukuba-shi, JP) ; TOKUMOTO; Seiji; (Tsukuba-shi,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HISAMITSU PHARMACEUTICAL CO., INC. |
Tosu- Shi |
|
JP |
|
|
Family ID: |
55459162 |
Appl. No.: |
16/668066 |
Filed: |
October 30, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15509398 |
Mar 7, 2017 |
|
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|
PCT/JP2015/075729 |
Sep 10, 2015 |
|
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16668066 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2037/0053 20130101;
A61L 2300/252 20130101; A61K 47/183 20130101; A61M 2037/0046
20130101; A61M 37/00 20130101; A61K 9/0021 20130101; A61M 2037/0023
20130101; A61L 31/16 20130101; A61L 31/08 20130101; A61M 37/0015
20130101 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61K 9/00 20060101 A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 11, 2014 |
JP |
2014-185149 |
Claims
1-9. (canceled)
10. A method for producing a microneedle device comprising the
steps of: providing a microneedle array comprising a substrate and
a microneedle; mixing a physiologically active substance, arginine,
and glycerin to obtain a coating composition; coating the
microneedle with the coating composition; and drying the coating
composition to form a coating layer on the microneedle.
11. The method according to claim 10, wherein the coating
composition further contains an acid selected from the group
consisting of citric acid, phosphoric acid, boric acid, tartaric
acid, and lactic acid.
12. The method according to claim 10, wherein the drying is
performed until, in the coating layer, the mass of arginine reaches
0.06 to 0.85-fold of the mass of the physiologically active
substance and the mass of glycerin reaches 40% or less relative to
the mass of the whole coating layer.
13. The method according to claim 11, wherein the drying is
performed until, in the coating layer, the mass of arginine reaches
0.06 to 0.85-fold of the mass of the physiologically active
substance and the mass of glycerin reaches 40% or less relative to
the mass of the whole coating layer.
Description
TECHNICAL FIELD
[0001] The present invention relates to a microneedle device.
BACKGROUND ART
[0002] A microneedle device is known as one of the devices for
intradermal administration of a physiologically active substance.
The microneedle device has a plurality of microneedles on its main
surface. As one specific aspect thereof, for example, there is a
microneedle having a coating layer containing a physiologically
active substance formed thereon and a self-dissolving microneedle
containing a physiologically active substance (for example, Patent
Literatures 1 to 4).
CITATION LIST
Patent Literature
[0003] Patent Literature 1: WO 2011/105496 [0004] Patent Literature
2: WO 2012/115207 [0005] Patent Literature 3: WO 2012/115208 [0006]
Patent Literature 4: JP 2014-507473 A
SUMMARY OF INVENTION
Technical Problem
[0007] In the case of a microneedle device in which a coating layer
containing a physiologically active substance is formed on each
microneedle, it is difficult to reproducibly apply the
physiologically active substance to the coating layer of each
microneedle so that the content of the substance is uniform.
[0008] When a coating agent is applied to form a coating layer, the
coating layer may be cracked due to the components in the coating
agent. Thus, it may be difficult to obtain sufficient strength for
applying to the skin.
[0009] Therefore, an object of the present invention is to provide
a microneedle device having a coating layer in which coating can be
performed so that a physiologically active substance in the coating
layer is uniformly dispersed and the occurrence of cracks in the
coating layer can be reduced when the coating layer is formed.
Solution to Problem
[0010] The present invention provides a microneedle device
comprising: a substrate; a microneedle disposed on the substrate;
and a coating layer formed on the microneedle; wherein the coating
layer contains a physiologically active substance, arginine, and
glycerin.
[0011] The coating layer contains glycerin so that the same amount
of the physiologically active substance can be reproducibly applied
to the microneedles.
[0012] It is preferable that, in the coating layer, the mass of
arginine is 0.06 to 0.85-fold of the mass of the physiologically
active substance and the mass of glycerin is 40% or less relative
to the mass of the whole coating layer. It is preferable that the
coating layer further contains an acid selected from the group
consisting of citric acid, phosphoric acid, boric acid, tartaric
acid, and lactic acid.
[0013] Further, the present invention provides a method for
producing a microneedle device including the steps of: providing a
microneedle array having a substrate and a microneedle; mixing a
physiologically active substance, arginine, and glycerin to obtain
a coating composition; coating the microneedle with the coating
composition; and drying the coating composition to form a coating
layer on the microneedle.
[0014] It is preferable that the coating composition further
contains an acid selected from the group consisting of citric acid,
phosphoric acid, boric acid, tartaric acid, and lactic acid.
[0015] It is preferable that the drying is performed until, in the
coating layer, the mass of arginine reaches 0.06 to 0.85-fold of
the mass of the physiologically active substance and the mass of
glycerin reaches 40% or less relative to the mass of the whole
coating layer.
[0016] Further, the present invention provides a coating agent for
microneedles containing a physiologically active substance,
arginine, and glycerin. It is preferable that the coating agent
further contains an acid selected from the group consisting of
citric acid, phosphoric acid, boric acid, tartaric acid, and lactic
acid.
[0017] The present invention also provides a method comprising a
step of coating each microneedle with a coating composition
containing a physiologically active substance, arginine, and
glycerin to form a coating layer, wherein the occurrence of cracks
in the coating layer on each microneedle is reduced. It is
preferable that the coating composition further contains an acid
selected from the group consisting of citric acid, phosphoric acid,
boric acid, tartaric acid, and lactic acid.
[0018] The present invention also provides a method comprising a
step of coating each microneedle with a coating composition
containing a physiologically active substance, arginine, and
glycerin to form a coating layer, wherein the content of the
components contained in the coating layer on each microneedle is
uniformly dispersed. It is preferable that the coating composition
further contains an acid selected from the group consisting of
citric acid, phosphoric acid, boric acid, tartaric acid, and lactic
acid.
Advantageous Effects of Invention
[0019] According to the present invention, the same amount of the
physiologically active substance can be reproducibly applied to the
microneedles. Further, according to the present invention, when the
coating layer is formed, the occurrence of cracks of the coating
layer can be reduced, thereby improving the productivity of the
microneedle device.
BRIEF DESCRIPTION OF DRAWINGS
[0020] FIG. 1 is a perspective view showing one embodiment of a
microneedle device.
[0021] FIG. 2 is a cross-sectional side surface view of FIG. 1
taken along the line II-II.
[0022] FIGS. 3(a) to 3(c) are pattern diagrams showing one
embodiment of a method for producing a microneedle device.
DESCRIPTION OF EMBODIMENTS
[0023] Hereinbelow, preferable embodiments will be explained with
reference to drawings. It is to be noted that in the explanation of
the drawings, the same symbols are assigned to the same elements
and redundant explanation will be omitted. Also, in the drawings,
some parts are exaggeratedly drawn to make understanding easy, and
thus the size and ratio are not necessarily consistent with the
description.
[0024] One embodiment of the present invention is a microneedle
device comprising: a substrate; a microneedle disposed on the
substrate; and a coating layer formed on the microneedle; wherein
the coating layer contains a physiologically active substance,
arginine, and glycerin.
[0025] FIG. 1 is a perspective view showing one embodiment of a
microneedle device. A microneedle device 1 shown in FIG. 1 has a
substrate 2, a plurality of microneedles 3 that are
two-dimensionally arranged on the substrate 2, and a coating layer
5 formed on each of the microneedles 3. The coating layer 5
contains a physiologically active substance, arginine, and
glycerin.
[0026] The substrate 2 is a foundation to support the microneedles
3. The area of the substrate 2 is preferably 0.5 to 10 cm.sup.2,
more preferably 1 to 5 cm.sup.2, and still more preferably 1 to 3
cm.sup.2. A substrate of a desired size may be configured by
connecting a plurality of the substrates 2.
[0027] The microneedles 3 each have a minute structure, and the
height (length) thereof is preferably 50 to 600 .mu.m. At this
point, the length of the microneedles 3 is set at 50 .mu.m or more,
thereby ensuring administration of the physiologically active
substance contained in the coating layer. Further, the length of
the microneedles 3 is set at 600 .mu.m or less, thereby avoiding
that the microneedles contact nerves so as to reduce the
possibility of pain and avoid the possibility of bleeding. Also,
when the length of the microneedles 3 is 500 .mu.m or less, the
amount of the physiologically active substance to enter the skin
can be efficiently administered, and in certain cases,
administrating without piercing the basement membrane is also
possible. The length of the microneedles 3 is particularly
preferably 300 to 500 .mu.m.
[0028] At this point, a microneedle 3 refers to a projecting
structure including, in a broad sense, a needle shape or a
structure including a needle shape. However, the microneedle is not
limited to a structure of a needle shape having a tapered tip, and
may also be a structure lacking a tapered tip. When the
microneedles 3 each have a conical structure, the diameter of the
basal surface thereof is preferably about 50 to 200 .mu.m. Although
the microneedles 3 are each in a conical shape according to the
present embodiment, microneedles may be in a polygonal pyramid
shape such as a square pyramid or in other shapes.
[0029] The microneedles 3 are each typically disposed spaced apart
so as to have a density of approximately 1 to 10 needles per
millimeter (mm) in a row of the needles. Generally, adjacent rows
are spaced apart from each other by a distance substantially equal
to the space between the needles in a row, and the microneedles 3
have a needle density of 100 to 10000 needles per cm.sup.2. When a
needle density of 100 needles or more is achieved, the microneedles
can efficiently pierce the skin. Meanwhile, a needle density of
more than 10000 needles makes it difficult to maintain the strength
of the microneedles 3. The density of the microneedles 3 is
preferably 200 to 5000 needles, more preferably 300 to 2000
needles, and still more preferably 400 to 850 needles.
[0030] Examples of a material of the substrate 2 or the
microneedles 3 include silicon, silicon dioxide, ceramics, metals
(such as stainless steel, titanium, nickel, molybdenum, chromium,
and cobalt) and synthetic or natural resin materials. In
consideration of the antigenicity of the microneedles and the unit
price of the material, a biodegradable polymer such as polylactic
acid, polyglycolide, polylactic acid-co-polyglycolide, pullulan,
caprolactone, polyurethane, and polyanhydride, and a synthetic or
natural resin material such as polycarbonate, polymethacrylic acid,
ethylenevinyl acetate, polytetrafluoroethylene, and
polyoxymethylene, which are non-degradable polymers, are
particularly preferable. Further, polysaccharides such as
hyaluronic acid, sodium hyaluronate, pullulan, dextran, dextrin,
and chondroitin sulfate are also suitable.
[0031] Examples of a production method of the substrate 2 or the
microneedles 3 include wet etching process or dry etching process
using a silicon substrate, precision machining using metals or
resins (such as electric discharge method, laser processing, dicing
processing, hot embossing process, and injection mold processing),
and machinery cutting. By these processing methods, the substrate 2
and the microneedles 3 are integrally molded. Examples of a method
for hollowing the microneedles 3 include a method in which a
secondary processing such as laser processing is applied after
producing the microneedles 3.
[0032] Although the microneedle device 1 has the coating layer 5 on
each of the microneedles 3, the coating layer 5 is preferably
formed by coating with the coating composition. Examples of the
coating method include spray coating and dip coating, and the dip
coating is preferable. In this regard, although the coating layer 5
is formed on all the microneedles 3 in FIG. 1, the coating layer 5
may be formed on only some of the microneedles 3. Although the
coating layer 5 is formed on only the tip portion of the
microneedle 3 in FIG. 1, the layer may be formed so as to cover the
whole microneedle 3. Further, the coating layer 5 may be formed on
the substrate 2.
[0033] FIG. 2 is a cross-sectional side surface view of FIG. 1
taken along the line II-II. As shown in FIG. 2, the microneedle
device 1 has the substrate 2, the microneedles 3 disposed on the
substrate 2, and the coating layer 5 formed on each of the
microneedles 3. The coating layer 5 formed on each of the
microneedles contains a physiologically active substance, arginine,
and glycerin.
[0034] The mass of arginine contained in the coating layer is
preferably 0.06 to 0.85-fold, more preferably 0.1 to 0.65-fold,
still more preferably 0.1 to 0.5-fold of the mass of the
physiologically active substance. The mass of arginine is 0.06-fold
or more of the mass of the physiologically active substance,
whereby the occurrence of cracks in the coating layer can be
reduced when the coating layer is formed. Consequently, the
productivity of the microneedle device is further improved.
[0035] Further, the mass of arginine contained in the coating layer
is preferably 0.1 to 40%, more preferably 3 to 33%, and still more
preferably 7 to 25% relative to the mass of the whole coating
layer.
[0036] The mass of glycerin contained in the coating layer is 40%
or less based on the mass of the whole coating layer. From the
viewpoint of practical utility, it is 10% or more. Further, the
mass of glycerin is preferably 10 to 40%, more preferably 15 to
40%, and still more preferably 15 to 35%.
[0037] The mass of glycerin contained in the coating layer is
preferably 2-fold or less, more preferably 1.5-fold or less, and
still more preferably 1-fold or less of the mass of the
physiologically active substance.
[0038] With respect to the mass of each of the components contained
in the coating layer, the content of glycerin is measured by, for
example, gas chromatography, and based on its value, the content of
other components can be calculated.
[0039] The coating layer can be formed using, for example, a
coating composition containing a physiologically active substance,
arginine and glycerin.
[0040] The physiologically active substance is not particularly
limited as long as it is a substance which exerts a therapeutic or
prophylactic effect in a subject to be administered. Examples of
the physiologically active substance include peptides, proteins,
DNAs, RNAs, sugars, nucleic acids, and glycoproteins. Particularly,
when the physiologically active substance is a glycoprotein, the
coating layer can be formed more efficiently.
[0041] Specific examples of the physiologically active substance
include interferon-.alpha., interferon-n for multiple sclerosis,
erithropoietin, follitropin-.beta., follitropin-.alpha., G-CSF,
GM-CSF, human chorionic gonadotropin, leutinizing hormone, follicle
stimulating hormone (FSH), calcitonin salmon, glucagon, GNRH
antagonist, insulin, LHRH (luteal hormone releasing hormone), human
growth hormone, parathyroid hormone, filgrastim, heparin, low
molecular weight heparin, somatropin, incretin, GLP-1 analog (for
example, exenatide, liraglutide, lixisenatide, albiglutide, and
taspoglutide), venom peptide analog, .gamma.-globulin, Japanese
encephalitis vaccine, rotavirus vaccine, Alzheimer's disease
vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine
vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine,
Lyme disease vaccine, rabies vaccine, diplococcus-pneumoniae
vaccine, yellow fever vaccine, cholera vaccine, vaccinia vaccine,
tuberculosis vaccine, rubella vaccine, measles virus vaccine,
influenza vaccine, mumps vaccine, botulinus vaccine, herpesvirus
vaccine, other DNA vaccines, and hepatitis B vaccine.
[0042] The content of the physiologically active substance in the
coating composition is preferably 20 to 70% by mass, more
preferably 25 to 50% by mass, and still more preferably 20 to 45%
by mass based on the mass of the whole coating composition. When
the content of the physiologically active substance is 20% by mass
or more, a pharmacological action of the physiologically active
substance is sufficiently exerted, thereby easily producing a
desired therapeutic effect.
[0043] The content of arginine in the coating composition is
preferably 0.05 to 2-fold, more preferably 0.05 to 1-fold, and
still more preferably 0.1 to 0.5-fold of the mass of the
physiologically active substance contained in the coating
composition. The content of arginine is 0.05-fold or more of the
mass of the physiologically active substance, thereby making cracks
in the coating layer less likely to occur. Further, the content of
arginine is 2-fold or less, thereby further improving the
solubility of the physiologically active substance in the coating
composition.
[0044] The coating composition contains glycerin so that the
content uniformity of the physiologically active substance in the
coating composition under the coating conditions (for example, room
temperature) is improved. Here, the phrase "lack of content
uniformity" means that when the coating composition is applied to
the microneedles, the content of the physiologically active
substance in the coating composition becomes non-uniform with
remarkable changes in physical properties of the coating
composition due to volatilization of a solvent (for example, a
phenomenon such as generation of concentration gradient or
impossibility of applying to microneedles after drying). The
content uniformity of the physiologically active substance is
improved, whereby the physiologically active substance is stably
released from the coating layer during the use of the microneedle
device and a desired therapeutic effect can be continuously
obtained. Further, glycerin having a high viscosity is contained so
that the coating layer is easily supported on the tip of the
microneedle. In this regard, glycerin is a component that
volatilizes when reduced-pressure drying is performed. The glycerin
itself does not solidify.
[0045] The content of glycerin in the coating composition is
preferably 0.8 to 2-fold, more preferably 1 to 2-fold, and still
more preferably 1 to 1.5-fold of the mass of the physiologically
active substance contained in the coating composition. More
preferred is a case in which the content of glycerin is 0.8-fold or
more of the mass of the physiologically active substance, because
the content uniformity and solubility of the physiologically active
substance in the coating layer are excellent and the dripping is
less likely to occur when being applied to the microneedles.
[0046] Further, the coating composition preferably contains an acid
selected from the group consisting of citric acid, phosphoric acid,
boric acid, tartaric acid, and lactic acid. Particularly, the
coating composition more preferably contains citric acid. The
coating composition contains a specific acid so that the basicity
of arginine can be neutralized, and the pH of the composition can
be adjusted to a desired range.
[0047] The content of the acid is preferably 0.1 to 20% by mass,
more preferably 0.5 to 10% by mass, and still more preferably 1 to
7% by mass based on the mass of the whole coating composition.
[0048] Further, the content of the acid is preferably 0.01 to
1-fold, more preferably 0.05 to 0.8-fold, and still more preferably
0.1 to 0.5-fold of the mass of arginine contained in the coating
composition.
[0049] The coating composition may further contain a solvent, a
polymeric carrier (thickening agent), a solubilizing agent, an
absorption promoter, a stabilizer, an antioxidant, an emulsifier, a
surfactant, and a compound such as a salt, as needed. Examples of
the solvent include water such as purified water and distilled
water and alcohols such as methanol and ethanol. The coating
composition contains a solvent so that the handling properties when
applied to the microneedles can be improved and the solvent can be
easily removed by the drying step.
[0050] When the coating composition contains a solvent, the solvent
is removed in the drying step. Accordingly, the composition ratio
of the components in the coating composition is not necessarily
reflected in the coating layer.
[0051] Hence, when a microneedle device is produced, the coating
layer is formed by drying the coating composition applied to the
microneedles. In the drying step, the solvent contained in the
coating composition is removed and the content of glycerin may also
decrease. Further, the coating layer is formed by reduced-pressure
drying, whereby the content of glycerin decreases and the
concentration of the physiologically active substance contained in
the coating layer tends to increase.
[0052] With respect to the time required to dry the applied coating
composition, the drying is preferably performed until the mass of
glycerin reaches 40% or less relative to the mass of the whole
coating layer. Specifically, the mass of glycerin decreases,
preferably by 25% or more, more preferably by 33% or more, and
still more preferably by 50% or more relative to the mass of
glycerin contained in the composition applied to the microneedles.
Further, the drying time is preferably 1 hour or longer, the drying
is performed more preferably for 3 hours or longer, still more
preferably 5 hours or longer, particularly preferably 10 hours or
longer, and extremely preferably 15 hours or longer.
[0053] Examples of the polymeric carrier include polyethylene
oxide, polyhydroxymethylcellulose, hydroxypropylcellulose,
polyhydroxypropylmethylcellulose, polymethylcellulose, dextran,
polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone,
pullulan, carmellose sodium, chondroitin sulfate, hyaluronic acid,
dextran, and gum arabic. The weight average molecular weight of
polyethylene glycol to be used as a polymeric carrier preferably
exceeds 600 but is 500000 or less. As the polymeric carrier, a
carrier highly compatible (having properties of being uniformly
mixed) with a physiologically active substance is preferable.
Particularly preferred are hydroxypropylcellulose, dextran,
polyvinyl alcohol, pullulan, and the like.
[0054] The content of the polymeric carrier in the coating
composition 10 is 0.005 to 30% by mass, preferably 0.01 to 20% by
mass, and more preferably 0.05 to 10% by mass based on the total
mass of the coating composition 10. The polymeric carrier may need
to have a certain degree of viscosity that does not cause dripping
and the viscosity is preferably 100 to 100000 mPas at room
temperature (25.degree. C.). A more preferable viscosity is 500 to
60000 mPas.
[0055] In addition to the above, to the coating composition 10,
propylene carbonate, crotamiton, L-menthol, peppermint oil,
limonene, diisopropyl adipate, and the like may be added as a
solubilizing aid or absorption promoter, and methyl salicylate,
glycol salicylate, L-menthol, thymol, peppermint oil, nonylic acid
vanillylamide, chili pepper extract, and the like may be added as
an efficacy supplement as needed.
[0056] The surfactant may be either a nonionic surfactant or an
ionic surfactant (cationic, anionic, and amphoteric); however, from
the safety aspect, a nonionic surfactant, which is normally used
for a pharmaceutical base, is desirable. Examples of these
compounds include sugar alcohol fatty acid ester such as sucrose
fatty acid ester, propylene glycol fatty acid ester,
polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin
fatty acid ester, polyethylene glycol fatty acid ester,
polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor
oil.
[0057] A method for producing a microneedle device comprises the
steps of: providing a microneedle array that has a substrate and a
microneedle; mixing a physiologically active substance, arginine,
and glycerin to obtain a coating composition; coating the
microneedle with the coating composition; and drying the coating
composition to form a coating layer on the microneedle.
[0058] Subsequently, the method for producing a microneedle device
will be explained with reference to FIGS. 3(a) to 3(c). In this
regard, the production method shown in FIGS. 3(a) to 3(c) is also
referred to as "dip method using a mask plate".
[0059] FIGS. 3(a) to 3(c) are pattern diagrams showing one
embodiment of a method for producing a microneedle device.
According to this method, first of all, as shown in FIG. 3(a), the
coating composition 10 is swept with a spatula 12 in the direction
of the arrow A on a mask plate 11. By doing so, openings 13 are
filled with the coating composition 10. Subsequently, as shown in
FIG. 3(b), the microneedles 3 are inserted into the openings 13 of
the mask plate 11. Thereafter, as shown in FIG. 3(c), the
microneedles 3 are pulled out from the openings 13 of the mask
plate 11. By doing so, the coating composition 10 adheres to the
microneedles 3. In this regard, the coating composition 10 may
adhere to the substrate 2. The volatile substance in the coating
composition 10 on the microneedles 3 is removed by a method such as
air drying, reduced-pressure drying (vacuum drying), or a
combination of these methods. By the above process, the coating
layer 5 strongly adheres to each of the microneedles 3, and
typically becomes glassy or solid, whereby the microneedle device 1
is produced. The water content in the coating layer 5 is normally
55% by mass or less, preferably 30% by mass or less, and more
preferably 10% by mass or less based on the total amount of the
coating layer 5. By the above method, dripping of the coating
composition 10 after being coated is prevented. The dripping
indicates dripping of the coating composition from needle tips and
means that an H part in FIG. 3(c) lengthens.
[0060] The height H of the coating layer 5 formed on each of the
microneedles 3 is adjusted by a clearance (gap) C shown in FIG.
3(b). This clearance C is defined as a distance between the basal
surface of the microneedles 3 and the surface of the mask plate 11
(a thickness of the substrate 2 is not involved), and is set
according to a tension of the mask plate 11 and the length of the
microneedles 3. The range of the distance of clearance C is
preferably 0 to 500 .mu.m. When a distance of clearance C is 0, it
means that the coating composition 10 is applied to the entire
microneedles 3. Although the height H of the coating composition 10
formed on the microneedles 3 varies depending on the height H of
the microneedles 3, the height H is normally 10 to 500 .mu.m,
preferably 30 to 300 .mu.m, and more preferably 40 to 250 .mu.m. In
order to effectively administer the physiologically active
substance in the coating composition 10 to the skin, the substance
is preferably concentrated in a part of the microneedle 3 (i.e.,
the tip portion of the microneedle 3). From viewpoints of the
stimulation to the skin and the transferring efficiency of the
physiologically active substance to the skin, it is preferable to
allow the substance to be located at up to 200 .mu.m from the tip
of the microneedle 3. When the coating composition 10 has a high
viscosity, the coating layer 5 is easily formed on a part of the
microneedle. By the method, the coating composition 10 adhering to
the microneedles 3 after removal of its volatile components can
form preferably an approximately spherical or teardrop shaped
coating layer 5 at the tip portion of the microneedle 3. Then, the
coating composition is inserted into the skin at the same time when
the microneedles 3 pierce the skin.
[0061] The thickness of the dried coating layer 5 is preferably
less than 50 .mu.m, more preferably less than 40 .mu.m, and still
more preferably 1 to 30 .mu.m. Generally, the thickness of the
coating layer 5 refers to an average thickness as measured over the
surface of the microneedle 3 after drying. The thickness of the
coating layer 5 can be optionally increased by applying a plurality
of films of the coating composition 10, namely, by repeatedly
performing the step of coating with the coating composition 10.
[0062] When the microneedle 3 is coated with the coating
composition 10, temperature and humidity in an installation
environment of an apparatus are preferably controlled at a constant
level. When the coating composition 10 contains water, the
environment may be filled with water, as needed. By doing so,
evaporation of the water in the coating composition 10 can be
prevented as much as possible.
EXAMPLE
[0063] Hereinbelow, the present invention will be more specifically
described by providing Examples.
[0064] (1) Content Uniformity Test
[0065] The coating compositions of Reference Examples 1 to 4
prepared according to the description of Table 1 were applied to
twenty microneedle sheets by the dip method using a mask plate. In
this regard, used physiologically active substances were dextran 40
(in Reference Examples 1 and 3), .gamma.-globulin (in Reference
Example 2), and bovine serum albumin (BSA) (in Reference Example
4). As a tracer, benzoic acid was added to each of Reference
Examples for HPLC measurement. Each number in Table 1 means mass
percent relative to the whole coating composition.
[0066] Subsequently, the coating compositions applied to the
microneedles were individually recovered. The content of benzoic
acid in each of the coating compositions was measured to calculate
the content of the physiologically active substance. The average,
standard deviation (SD), and coefficient of variation (CV) of the
content of the resulting physiologically active substance were
calculated. In this regard, the coefficient of variation (CV) is a
value obtained by dividing the standard deviation by the
average.
TABLE-US-00001 TABLE 1 Reference Reference Reference Reference
Example 1 Example 2 Example 3 Example 4 Dextran 40 49 -- 29 --
.gamma.-globulin -- 29 -- -- BSA -- -- -- 34 Glycerin -- 52.5 52.5
48.75 Water 50 17.5 17.5 16.25 Benzoic acid 1 1 1 1 Total 100 100
100 100
[0067] The results are shown in Table 2. In the case of using the
coating compositions of Reference Examples 2 to 4 containing
glycerin, both the standard deviation and coefficient of variation
decreased, compared to the case of using the coating composition of
Reference Example 1. Therefore, it is considered that the coating
composition contains glycerin so that the content uniformity of the
physiologically active substance in the coating layer is
improved.
TABLE-US-00002 TABLE 2 Reference Reference Reference Reference
Example 1 Example 2 Example 3 Example 4 Average [.mu.g] 47.2 15.8
52.1 33.5 Standard deviation 4.9 1.2 2.4 1.2 (SD) [.mu.g]
Coefficient of 10.3 7.3 4.7 3.7 variation (CV) [%]
[0068] (2) Influence of Content of Arginine
[0069] BSA, L-arginine, citric acid, glycerin, and water were mixed
according to the description of Table 3 to prepare coating
compositions of Examples 1 to 9 and Comparative Example 1. In this
regard, BSA was used as the physiologically active substance. Each
number in Table 3 means "% by mass". Each of the obtained coating
compositions was applied to the tip of the microneedle by the dip
method using a mask plate. Subsequently, each of the applied
coating compositions was dried under reduced pressure to form a
coating layer. The content of glycerin in the coating layer was
quantified by gas chromatography (GC) analysis. Further, the
property of the coating layer (crack state) was observed using the
digital microscope (KEYENCE CORPORATION.) and evaluated in
accordance with the following evaluation criteria:
[0070] <Evaluation Criteria>
[0071] Good: No cracks;
[0072] Poor: Any cracks are present on the surface; and
[0073] Bad: Any cracks are present on the surface and the coating
layer is partially chipped.
TABLE-US-00003 TABLE 3 L- Citric BSA arginine acid Glycerin Water
Total Comparative 50.0 -- -- 40.0 10.0 100.0 Example 1 Example 1
46.7 2.5 0.8 40.0 10.0 100.0 Example 2 43.3 5.0 1.7 40.0 10.0 100.0
Example 3 40.0 7.5 2.5 40.0 10.0 100.0 Example 4 36.7 10.0 3.3 40.0
10.0 100.0 Example 5 33.3 12.5 4.2 40.0 10.0 100.0 Example 6 30.0
15.0 5.0 40.0 10.0 100.0 Example 7 26.7 17.5 5.8 40.0 10.0 100.0
Example 8 23.3 20.0 6.7 40.0 10.0 100.0 Example 9 40.0 10.0 -- 40.0
10.0 100.0
[0074] The results are shown in Table 4. In the cases of the
coating compositions of Examples 1 to 9 containing L-arginine, the
occurrence of cracks was reduced during formation of the coating
layer. The occurrence of cracks was significantly reduced,
particularly in the cases of the coating compositions of Examples 2
to 9 having an L-arginine content of 7.3% by mass or more. During
preparation of the coating compositions of Examples 1 to 7, the
solubility of BSA, L-arginine, and citric acid in a mixed solvent
of glycerin and water (volume ratio 4:1) was more excellent.
TABLE-US-00004 TABLE 4 Content [% by mass] BSA L-arginine Glycerin
Cracks Comparative 74.8 0.0 25.2 x Example 1 Example 1 71.0 3.8
24.0 .DELTA. Example 2 63.0 7.3 27.3 .smallcircle. Example 3 62.4
11.7 22.0 .smallcircle. Example 4 58.6 16.0 20.1 .smallcircle.
Example 5 54.5 20.4 18.3 .smallcircle. Example 6 50.1 25.0 16.5
.smallcircle. Example 7 44.1 29.0 17.2 .smallcircle. Example 8 39.1
33.5 16.3 .smallcircle. Example 9 62.4 15.6 22.0 .smallcircle.
[0075] (3) Effect of Reducing Occurrence of Cracks
[0076] A physiologically active substance, L-arginine, citric acid,
and aqueous glycerin were mixed according to the description of
Table 5 to prepare coating compositions of Examples 10 to 13 and
Comparative Examples 2 to 5. In this regard, human serum albumin
(HSA), lixisenatide, luteinizing hormone-releasing hormone (LHRH),
or .gamma.-globulin was used as the physiologically active
substance. Further, the used aqueous glycerin has a weight ratio of
water to glycerin of 20:80. Each number in Table 5 means "% by
mass". Each of the obtained coating compositions was applied to the
tip of the microneedle by the dip method using a mask plate.
Subsequently, each of the applied coating compositions was dried
under reduced pressure to form a coating layer. The content of
glycerin in the coating layer was quantified by gas chromatography
(GC) analysis. Further, the property of the coating layer (crack
state) was observed using the digital microscope (KEYENCE
CORPORATION.) and evaluated in accordance with the above evaluation
criteria.
TABLE-US-00005 TABLE 5 Physiologically active substance Citric
Aqueous Kind Content L-arginine acid glycerin Comparative HSA 30.0
0.0 0.0 70.0 Example 2 Example 10 HSA 30.0 3.5 1.2 65.3 Comparative
Lixisenatide 40.0 0.0 0.0 60.0 Example 3 Example 11 Lixisenatide
40.0 4.6 1.5 53.9 Comparative LHRH 50.0 0.0 0.0 50.0 Example 4
Example 12 LHRH 50.0 5.8 1.9 42.3 Comparative .gamma.-globulin 30.0
0.0 0.0 70.0 Example 5 Example 13 .gamma.-globulin 30. 3.5 1.2
65.3
[0077] The results are shown in Table 6. As shown in Table 6, when
HSA, lixisenatide, LHRH or .gamma.-globulin was used as the
physiologically active substance, cracks were not generated in the
coating compositions of Examples 10 to 13 containing L-arginine and
citric acid during formation of the coating layer. Meanwhile,
cracks were generated in the coating compositions of Comparative
Examples 2 to 5 which did not contain L-arginine and citric acid
during formation of the coating layer.
TABLE-US-00006 TABLE 6 Content ratio of L-arginine to Content
physiologically active [%] of substance glycerin Cracks Comparative
-- 13.2 x Example 2 Example 10 0.12 17.9 .smallcircle. Comparative
-- 15.4 x Example 3 Example 11 0.12 19.7 .smallcircle. Comparative
-- 23.0 x Example 4 Example 12 0.12 28.1 .smallcircle. Comparative
-- 11.2 x Example 5 Example 13 0.12 13.6 .smallcircle.
[0078] The coating compositions of Examples 14 to 20 were prepared
according to the description of Table 7.
TABLE-US-00007 TABLE 7 Physiologically active substance Citric
Aqueous Kind Content L-arginine acid glycerin Comparative
Parathyroid 40.0 5.0 1.5 53.5 Example 14 hormone Comparative GLP-1
analog 40.0 5.0 1.5 53.5 Example 15 Comparative Interferon-.beta.
40.0 5.0 1.5 53.5 Example 16 Comparative Low molecular 40.0 5.0 1.5
53.5 Example 17 weight heparin Comparative Venom peptide 40.0 5.0
1.5 53.5 Example 18 analog Comparative Influenza 40.0 5.0 1.5 53.5
Example 19 vaccine Comparative Cancer vaccine 40.0 5.0 1.5 53.5
Example 20
[0079] (4) Content Uniformity Test
[0080] The coating composition of Example 21 prepared according to
the description of Table 8 was applied to twenty microneedle sheets
by the dip method using a mask plate. In this regard, bovine serum
albumin (BSA) was used as the physiologically active substance and
a tracer (fluorescein sodium) was added thereto for measurement
with a fluorescence plate reader. Further, each number in Table 8
means mass percent relative to the whole coating composition.
[0081] Subsequently, the coating compositions applied to
microneedles were respectively recovered. The content of
fluorescein sodium in each of the coating compositions was measured
to calculate the content of the physiologically active substance.
The average, standard deviation (SD), and coefficient of variation
(CV) of the content of the resulting physiologically active
substance were calculated. In this regard, the coefficient of
variation (CV) is a value obtained by dividing the standard
deviation by the average.
TABLE-US-00008 TABLE 8 Example 21 BSA 30 Glycerin 60 Arginine 5
Water 15 Fluorescein sodium 0.05
[0082] The results are shown in Table 9. The formation of the
coating layer using the coating composition of Example 21 resulted
in an improvement of the content uniformity of the physiologically
active substance in the coating layer.
TABLE-US-00009 TABLE 9 Example 21 Average [.mu.g] 36.7 Standard
deviation (SD) 2.6 [.mu.g] Coefficient of variation 7.2 (CV)
[%]
[0083] (5) Effect of Reducing Occurrence of Cracks
[0084] A physiologically active substance, L-arginine, acid, and
aqueous glycerin were mixed according to the description of Tables
10 and 11 to prepare coating compositions of Examples 25 to 32. In
this regard, human serum albumin (HSA), lixisenatide, luteinizing
hormone-releasing hormone (LHRH) or .gamma.-globulin was used as
the physiologically active substance, and phosphoric acid or
tartaric acid was used as the acid. Further, the used aqueous
glycerin has a weight ratio of water to glycerin of 20:80. Each
number in Tables 10 and 11 means "% by mass". Each of the obtained
coating compositions was applied to the tip of the microneedle by
the dip method using a mask plate. Subsequently, each of the
applied coating compositions was dried under reduced pressure to
form a coating layer. The content of glycerin in the coating layer
was quantified by gas chromatography (GC) analysis. Further, the
property of the coating layer (crack state) was observed using the
digital microscope (KEYENCE CORPORATION.) and evaluated in
accordance with the above evaluation criteria.
TABLE-US-00010 TABLE 10 Physiologically active Phosphoric Aqueous
substance Arginine acid glycerin Example 25 HSA 30 3.5 1.2 65.3
Example 26 Lixisenatide 40 4.6 1.5 53.9 Example 27 LHRH 50 5.8 1.9
42.3 Example 28 .gamma.-globulin 30 3.5 1.2 65.3
TABLE-US-00011 TABLE 11 Physiologically active Tartaric substance
Arginine acid Glycerin Example 29 HSA 30 1.5 1.2 65.3 Example 30
Lixisenatide 40 4.6 1.5 53.9 Example 31 LHRH 50 5.8 1.9 42.3
Example 32 .gamma.-globulin 30 3.5 1.2 65.3
[0085] The results are shown in Table 12. No cracks were generated
in all the coating layers prepared from the coating compositions of
Examples 25 to 32.
TABLE-US-00012 TABLE 12 Content ratio of L-arginine Content to
physiologically active [%] of substance glycerin Cracks Example 25
0.12 16.3 .smallcircle. Example 26 0.12 21.8 .smallcircle. Example
27 0.12 22.6 .smallcircle. Example 28 0.12 18.6 .smallcircle.
Example 29 0.12 16.6 .smallcircle. Example 30 0.12 26.8
.smallcircle. Example 31 0.12 26.6 .smallcircle. Example 32 0.12
17.9 .smallcircle.
REFERENCE SIGNS LIST
[0086] 1 . . . Microneedle device, 2 . . . Substrate, 3 . . .
Microneedle, 5 . . . Coating layer, 10 . . . Coating composition,
11 . . . Mask plate, 12 . . . Spatula, 13 . . . Opening.
* * * * *