U.S. patent application number 11/883118 was filed with the patent office on 2008-10-23 for percutaneously absorbable preparation, percutaneously absorbable preparation holding sheet, and percutaneously absorbable preparation holding equipment.
This patent application is currently assigned to BIOSERENTACH CO., LTD.. Invention is credited to Kanji Takada.
Application Number | 20080262444 11/883118 |
Document ID | / |
Family ID | 36740525 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080262444 |
Kind Code |
A1 |
Takada; Kanji |
October 23, 2008 |
Percutaneously Absorbable Preparation, Percutaneously Absorbable
Preparation Holding Sheet, and Percutaneously Absorbable
Preparation Holding Equipment
Abstract
Self-dissolving needle-like or filamentous shape percutaneously
absorbable preparations, by which inherently poorly absorbable
drugs into the body through the skin is efficiently administered.
The preparations are made of at least one material selected from
the group consisting of proteins, polysaccharides, polyvinyl
alcohols, carboxyvinyl polymers and sodium polyacrylic acids. An
active substance contained therein is released in a
sustained-release fashion (1) by forming a water-insoluble layer on
its surface, (2) by holding the active substance in porous
materials, or (3) by imparting a long-acting characteristic to the
active substance. The present invention also provides a sheet-like
carrier for holding the preparations on at least one of the sides
thereof, and a piece of equipment for holding the preparations so
as to facilitate the administration of them.
Inventors: |
Takada; Kanji; (Kyoto,
JP) |
Correspondence
Address: |
WOOD, PHILLIPS, KATZ, CLARK & MORTIMER
500 W. MADISON STREET, SUITE 3800
CHICAGO
IL
60661
US
|
Assignee: |
BIOSERENTACH CO., LTD.
Kyoto-shi
JP
|
Family ID: |
36740525 |
Appl. No.: |
11/883118 |
Filed: |
January 30, 2006 |
PCT Filed: |
January 30, 2006 |
PCT NO: |
PCT/JP2006/301480 |
371 Date: |
July 26, 2007 |
Current U.S.
Class: |
514/1.1 ;
424/184.1; 514/44R; 514/54; 514/772.4; 514/773; 514/774; 514/776;
514/777; 514/779; 514/781 |
Current CPC
Class: |
A61K 38/21 20130101;
A61K 31/727 20130101; A61M 2037/0061 20130101; A61K 9/0021
20130101; A61P 37/00 20180101; A61M 37/0015 20130101; A61K 9/7007
20130101; A61P 5/50 20180101; A61K 31/375 20130101; A61P 3/10
20180101; A61K 38/28 20130101; A61M 2037/0046 20130101 |
Class at
Publication: |
604/288 ;
514/772.4; 514/773; 514/777; 514/776; 514/774; 514/781; 514/779;
514/2; 514/54; 514/44; 424/184.1; 514/3 |
International
Class: |
A61M 31/00 20060101
A61M031/00; A61K 47/32 20060101 A61K047/32; A61K 47/42 20060101
A61K047/42; A61K 47/36 20060101 A61K047/36; A61K 47/38 20060101
A61K047/38; A61K 38/02 20060101 A61K038/02; A61K 31/715 20060101
A61K031/715; A61K 48/00 20060101 A61K048/00; A61K 39/00 20060101
A61K039/00; A61K 38/28 20060101 A61K038/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 31, 2005 |
JP |
2005-023276 |
Oct 11, 2005 |
JP |
2005-296691 |
Claims
1. Percutaneously absorbable preparations having a base of
water-soluble and biologically soluble polymer material, and an
active substance held in the base, comprising: having a slender,
pointed shape, such as a needle-like or filamentous shape, adapted
for insertion into skin to percutaneously administer the active
substance into the body, wherein the polymer material is at least
one material selected from the group consisting of proteins,
polysaccharides, polyvinyl alcohols, carboxyvinyl polymers and
sodium polyacrylic acids
2.-28. (canceled)
29. The percutaneously absorbable preparations of claim 1, wherein
the protein is at least one material selected from the group
consisting of serum albumin, serum .alpha.-acid glycoprotein and
gelatin.
30. The percutaneously absorbable preparations of claim 1, wherein
the polysaccharide is at least one material selected from the group
consisting of glycogen, dextrin, dextran, dextran sulfate, sodium
chondroitin sulfate, hydroxy propyl cellulose, alginic acid,
agarose, chitin, chitosan, pullulan and hyaluronic acid.
31. The percutaneously absorbable preparations of claim 1, wherein
the base contains an absorption rate controller for controlling the
absorption rate of the active substance.
32. The percutaneously absorbable preparations of claim 31, wherein
the absorption rate controller is an absorption enhancer.
33. The percutaneously absorbable preparations of claim 32, wherein
the absorption enhancer is a surfactant.
34. The percutaneously absorbable preparations of claim 1, wherein
the active substance is a drug.
35. The percutaneously absorbable preparations of claim 34, wherein
the drug falls in peptides, proteins, nucleic acids,
polysaccharides or vaccine.
36. The percutaneously absorbable preparations of claim 1, wherein
the base contains a stabilizer for stabilizing the active
substance.
37. The percutaneously absorbable preparations of claim 1, further
comprising a moisture-proof layer formed on the surface
thereof.
38. The percutaneously absorbable preparations of claim 1, wherein
the preparations are constricted or have a secant in part on the
surface thereof.
39. The percutaneously absorbable preparations of claim 1, wherein
the preparations comprise at least two of them linked in
series.
40. Percutaneously absorbable preparations having a base of
water-soluble and biologically soluble polymer material, and an
active substance held in the base, comprising: having a slender,
pointed shape, such as a needle-like or filamentous shape, adapted
for insertion into skin to percutaneously administer the active
substance into the body, wherein the percutaneously absorbable
preparations have a water-insoluble layer formed on the surface
thereof, and wherein the active substance is released in a
sustained-release fashion.
41. The percutaneously absorbable preparations of claim 40, wherein
the water-insoluble layer is formed by a cross-link reaction.
42. The percutaneously absorbable preparations of claim 40, wherein
the polymer material is at least one material selected from the
group consisting of proteins, polysaccharides, polyvinyl alcohols,
carboxyvinyl polymers and sodium polyacrylic acids.
43. The percutaneously absorbable preparations of claim 40, wherein
the preparations comprise at least two of them linked in
series.
44. Percutaneously absorbable preparations having a base of
water-soluble and biologically soluble polymer material, and an
active substance held in the base, comprising: having a slender,
pointed shape, such as a needle-like or filamentous shape, adapted
for insertion into skin to percutaneously administer the active
substance into the body, wherein the base contains a porous
compound, and wherein the active substance is held in the porous
compound and is released in a sustained-release fashion.
45. The percutaneously absorbable preparations of claim 44, wherein
the porous material is at least one material selected from the
group consisting of calcium silicate, aluminum silicate, magnesium
silicate, anhydrous silicate, porous calcium carbonate, porous
calcium phosphate and porous silicon.
46. The percutaneously absorbable preparations of claim 44, wherein
the preparations comprise at least two of them linked in
series.
47. Percutaneously absorbable preparations having a base of
water-soluble and biologically soluble polymer material, and an
active substance held in the base, comprising: having a slender,
pointed shape, such as a needle-like or filamentous shape, adapted
for insertion into skin to percutaneously administer the active
substance into the body, wherein the active substance is a
long-acting material and is released in a sustained-release
fashion.
48. The percutaneously absorbable preparations of claim 47, wherein
the long-acting substance is long-acting type insulin or protein
cross-linked with polyethylene glycol.
49. The percutaneously absorbable preparations of claim 47, wherein
the preparations comprise at least two of them linked in
series.
50. A sheet-like carrier for holding at least one of the
percutaneously absorbable preparations of claim 1 on at least one
of the surfaces thereof, wherein the preparations held on the
carrier are inserted into the skin by pushing the carrier
thereonto.
51. A sheet-like carrier for holding at least one of the
percutaneously absorbable preparations of claim 40 on at least one
of the surfaces thereof, wherein the preparations held on the
carrier are inserted into the skin by pushing the carrier
thereonto.
52. A sheet-like carrier for holding at least one of the
percutaneously absorbable preparations of claim 44 on at least one
of the surfaces thereof, wherein the preparations held on the
carrier are inserted into the skin by pushing the carrier
thereonto.
53. A sheet-like carrier for holding at least one of the
percutaneously absorbable preparations of claim 47 on at least one
of the surfaces thereof, wherein the preparations held on the
carrier are inserted into the skin by pushing the carrier
thereonto.
54. Equipment for holding percutaneously absorbable preparations
comprising having a base of water-soluble and biologically soluble
polymer material, an active substance held in the base, and having
a slender, pointed shape, such as a needle-like or filamentous
shape, adapted for insertion into skin to percutaneously administer
the active substance into the body, the equipment comprising a main
body having a penetration hole in and along which the preparations
are moved.
55. Equipment for holding percutaneously absorbable preparations,
the equipment comprising a main body having a penetration hole in
and along which the preparations are moved, wherein the
preparations fall in claim 1.
56. Equipment for holding percutaneously absorbable preparations,
the equipment comprising a main body having a penetration hole in
and along which the preparations are moved, wherein the
preparations fall in claim 40.
57. Equipment for holding percutaneously absorbable preparations,
the equipment comprising a main body having a penetration hole in
and along which the preparations are moved, wherein the
preparations fall in claim 44.
58. Equipment for holding percutaneously absorbable preparations,
the equipment comprising a main body having a penetration hole in
and along which the preparations are moved, wherein the
preparations fall in claim 47.
59. The equipment of claim 54, wherein the penetration hole
accommodates a spacer kept in contact with the preparations held in
the penetration hole, so that the spacer moves in and along the
penetration hole while being kept in contact with the
preparations.
60. The equipment of claim 54, wherein the main body comprises a
concave to which the penetration hole is open.
61. The equipment of claim 60, wherein the concave comprises female
threads cut on the inside wall thereof.
62. The equipment of claim 54, wherein the main body is made of
plastics.
Description
TECHNICAL FIELD
[0001] The present invention relates to percutaneously absorbable
preparations per se, a sheet-like carrier for holding the
preparations, and a piece of equipment for holding the
preparations. More particularly, it relates to (1) a
self-dissolving percutaneously absorbable preparation having a
slender, pointed shape adapted for insertion into the skin, this
shape being hereinafter referred to as "needle-like or filamentous
shape", the preparations which include a base holding an active
substance of proteins and polysaccharides etc., (2) a sheet-like
carrier for holding the percutaneously absorbable preparations on
at least one of the sides thereof, and (3) a piece of equipment for
holding the preparations in a penetration hole formed in its main
body. In this specification, the term "preparations" in plural
means not only a product but also products, so as to distinguish
from "preparation" in singular meaning the act of preparing.
BACKGROUND ART
[0002] As one of the noninvasive methods for the administration of
drugs, a drug is administered with the use of percutaneously
absorbable preparations. For instance, percutaneously absorbable
preparations such as ointment, cream, lotion, poultice and patch
have been used. The use of these percutaneous preparations is
usually limited to the local therapy of disease localized on the
skin. Because of the barrier function possessed by the skin, the
systemic therapy with drugs through the percutaneous route is
difficult due to the low systemic availability of locally applied
drugs to the skin. Though several patch type Transdermal
Therapeutic Systems (TTS) have been launched onto the market, the
drugs are limited to estrogen, nitric acid derivatives, tulobuterol
and nicotine etc. that show their pharmacological activities at low
plasma or serum concentration, i.e., their therapeutic
concentrations are lower than 20 ng/mL. So far, the absorption of
macromolecular drugs such as insulin through percutaneous route is
difficult because of their low skin permeability and no
percutaneous preparations have been developed up to now. Therefore,
macromolecular drugs are still administered to patients by
injections.
[0003] Under such a background, development of injection technology
with low invasion has been challenged and microneedle was developed
as one of those technologies. Microneedle is a fine needle having
no pain when is applied onto the skin. As microneedle material, not
only steel as a conventional injection needle but also silicon etc,
are used (Non-patent documents 1 and 2). These microneedles have
holes in themselves as conventional injection needles and drug
solutions are injected through these holes. In addition,
self-dissolving microneedle made of base material dissolving in the
body was also developed. Active substance is contained in the base
and is released from microneedle by the dissolution of the base
after inserted into the skin. For instance, a self-dissolving
microneedle made of maltose as the base is disclosed (Patent
document 1). In addition, the self-dissolving microneedles made of
polylactic acid, polyglycolic acid or poly-.epsilon.-caprolactone
are also known.
[0004] In addition, when the active substance is a drug that
receives high clearance from the systemic circulation such as
insulin, long-term pharmacological activity is needed. In such a
case, self-dissolving microneedle having the function of
sustained-release characteristics of the active substance is
required. For instance, a self-dissolving microneedle consisting of
polylactic acid has a sustained-release function of the active
substance.
[0005] Patent document 1: JP2003-238347 A
[0006] Non-patent document 1: D. K. Armini and C. Lui,
"Microfabrication technology for polycaprolactone, a biodegradable
polymer", Journal of Micromechanics and Microengineering, 2000, 10,
80-84
[0007] Non-patent document 2: M. R. Prausnitz, "Microneedles for
transdermal drug delivery", Advanced Drug Delivery Reviews, 2004,
56, 581-587
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0008] When a self-dissolving microneedle which has a base
consisting of maltose is prepared, an active substance is added to
the melt maltose heated to more than the melting point of maltose
and thereafter the mixture is molded. Here, the melting point of
maltose is high, about 102-103.degree. C. In a microneedle which
has a base consisting of maltose, an active substance to be held in
the base is therefore exposed to a high temperature during its
manufacturing process. However, there are many active substances
that receive degradation, denaturation or inactivation at a high
temperature. A self-dissolving microneedle of which base is maltose
is therefore difficult to contain these active substances.
Especially, when the active substances are peptides and proteins
which can escape neither denaturation nor inactivation by heating,
it is extremely difficult to use maltose as a base. When an active
substance is insulin, denaturation and inactivation by high
temperature is prevented in some degree by using insulin powder.
However, since molded maltose in which powder is dispersed is
fragile, a microneedle containing maltose as a base and insulin
powder held therein is difficult to keep its physical strength.
Further, since maltose has a strong hygroscopicity, a
self-dissolving microneedle which has a base consisting of maltose
adsorbs moisture as the time passes and the top of the microneedle
becomes soft. As a result, it has a pitfall, i.e. unavailability
for the insertion into the skin. Therefore, it may be difficult for
a self-dissolving microneedle containing maltose as a base to
administer an active substance quantitatively.
[0009] Still further, when polylactic acid, a water-insoluble
polymer, is used as a base for a microneedle to obtain
sustained-release characteristics of the active substance,
polylactic acid needs to be dissolved with an organic solvent such
as methylene chloride. However, some active substances receive
denaturation or inactivation by exposure to organic solvents. For
instance, when proteins or peptides such as insulin are employed as
an active substance, they are easily denaturated or inactivated by
exposure to an organic solvent. Therefore, a self-dissolving
microneedle which has a base consisting of a water-soluble material
and has sustained-release characteristics is desired.
[0010] The primary object of the present invention is to provide a
needle-like or filamentous shape self-dissolving percutaneously
absorbable preparation, hereinafter being sometimes referred to
merely as "preparations", having suitable physical strength for the
percutaneous delivery of poorly absorbable drugs through a
percutaneous route by producing at relatively low temperature
without the use of any organic solvent.
Means to Solve the Problems
[0011] To solve the above mentioned problems, the inventor has
succeeded to invent needle-like or filamentous shape
self-dissolving percutaneously absorbable preparations that are
prepared in room or under low temperature conditions through many
studies concerning the screening of the base materials. The
inventor has also succeeded to invent needle-like or filamentous
shape self-dissolving percutaneously absorbable preparations having
sustained-release characteristics of active substance without
polylactic acid. In addition, the inventor has succeeded in
preparing the percutaneously absorbable preparations holding
sheet-like carrier by which the percutaneously absorbable
preparations are administered percutaneously with high efficiency.
Furthermore, the inventor has completed this invention by preparing
percutaneously absorbable preparations holding equipment by which
needle-like or filamentous shape percutaneously absorbable
preparations are inserted into the skin with ease. The present
invention will be described hereinafter.
[0012] According to a first aspect of percutaneously absorbable
preparations of the present invention, percutaneously absorbable
preparations having a base of water-soluble and biologically
soluble polymer material, and an active substance held in the base
are characterized by having a slender, pointed shape, such as a
needle-like or filamentous shape, adapted for insertion into skin
to percutaneously administer the active substance into the body,
wherein the polymer material is at least one material selected from
the group consisting of proteins, polysaccharides, polyvinyl
alcohols, carboxyvinyl polymers and sodium polyacrylic acids.
[0013] The percutaneously absorbable preparations in this aspect
are a self-dissolving percutaneously absorbable type by which the
active substance is administered percutaneously into the body by
inserting the preparations into the skin, wherein the active
substance is held in the water-soluble and biologically soluble
macromolecular base. In the percutaneously absorbable preparations
in this aspect, the base is made of at least one material selected
from the group consisting of proteins, polysaccharides, polyvinyl
alcohols, carboxyvinyl polymers and sodium polyacrylic acids, and
the preparations have a needle-like or a filamentous shape. The
percutaneously absorbable preparations in this aspect can be made
at room temperature or at relatively low temperature, because the
base consists of protein etc. Therefore, the active substance can
be kept from exposure to high temperature during the manufacturing
process. More specifically, though the active substance is
inherently unstable at high temperature, it remains active during
the manufacturing process. As a result, the active substance is
highly efficiently administered percutaneously to the body by use
of the percutaneously absorbable preparations in this aspect.
[0014] Proteins, polysaccharides, polyvinyl alcohols, carboxyvinyl
polymers and sodium polyacrylic acids that are used as a base of
the percutaneously absorbable preparations in this aspect belong to
"thread-forming substance" that becomes glue when dissolved in a
small amount of water.
[0015] According to a second aspect of percutaneously absorbable
preparations of the present invention, percutaneously absorbable
preparations having a base of water-soluble and biologically
soluble polymer material, and an active substance held in the base,
are characterized by having a slender, pointed shape, such as a
needle-like or filamentous shape, adapted for insertion into skin
to percutaneously administer the active substance into the body,
wherein the percutaneously absorbable preparations have a
water-insoluble layer formed on the surface thereof, and wherein
the active substance is released in a sustained-release
fashion.
[0016] The advantage of the percutaneously absorbable preparations
in this aspect is in the capability of sustained-releasing the
active substance. More specifically, the percutaneously absorbable
preparations have a water-soluble and biologically soluble
macromolecular base and an active substance held in the base. The
active substance is percutaneously administered into the body,
wherein the preparation is provided with a water-insoluble layer
formed on its surface. In the percutaneously absorbable
preparations in this aspect, no organic solvent is used during the
manufacturing process of the base, because the base consists of
water-soluble materials. More specifically, since the active
substance held in the base is not exposed to organic solvent, the
active substance potentially keeps its activity during the
manufacturing process. As a result, the active substance is
percutaneously administered to the body highly efficiently by the
percutaneously absorbable preparations in this aspect. In addition,
the percutaneously absorbable preparations in this aspect are
easily manufactured as the active substance has sustained-release
characteristics by forming a water-insoluble layer on its
surface.
[0017] Preferably, the water-insoluble layer is formed by
cross-reaction.
[0018] The percutaneously absorbable preparations of the preferred
aspect are easily manufactured.
[0019] According to a third aspect of percutaneously absorbable
preparations of the present invention, percutaneously absorbable
preparations having a base of water-soluble and biologically
soluble polymer material, and an active substance held in the base,
are characterized by having a slender, pointed shape, such as a
needle-like or filamentous shape, adapted for insertion into skin
to percutaneously administer the active substance into the body;
wherein the base contains a porous compound, and wherein the active
substance is held in the porous compound and is released in a
sustained-release fashion.
[0020] Preferably, the porous material is at least one material
selected from the group consisting of calcium silicate, aluminum
silicate, magnesium silicate, anhydrous silicate, porous calcium
carbonate, porous calcium phosphate and porous silicon.
[0021] The percutaneously absorbable preparations in this aspect
are needle-like or filamentous shape self-dissolving percutaneously
absorbable preparations having a sustained-release function of the
active substance. More specifically, the percutaneously absorbable
preparations have a water-soluble and biologically soluble
macromolecular base and an active substance held in the base and
the active substance is percutaneously administered into the body,
wherein the active substance is held in porous materials contained
in the base. In the percutaneously absorbable preparations in this
aspect, no organic solvent is used during the manufacturing process
of the base, because the base consists of water-soluble materials.
More specifically, since the active substance held in the base is
kept from exposure to organic solvent, the active substance remains
active during the manufacturing process. As a result, the active
substance is administered percutaneously into the body highly
efficiently by the percutaneously absorbable preparations in this
aspect. In addition, the percutaneously absorbable preparations in
this aspect do not need a special treatment to allow the active
substance to possess sustained-release characteristics, because the
active substance is held in porous materials contained in the
base.
[0022] According to a fourth aspect of percutaneously absorbable
preparations of the present invention, percutaneously absorbable
preparations having a base of water-soluble and biologically
soluble polymer material, and an active substance held in the base,
is characterized by having a slender, pointed shape, such as a
needle-like or filamentous shape, adapted for insertion into skin
to percutaneously administer the active substance into the body,
wherein the active substance is a long-acting material and is
released in a sustained-release fashion.
[0023] Preferably, the long-acting substance is long-acting type
insulin or protein cross-linked with polyethylene glycol.
[0024] The percutaneously absorbable preparations in this aspect
have sustained-release characteristics of active substances. More
specifically, the percutaneously absorbable preparations have a
water-soluble biologically soluble macromolecular base and an
active substance held in the base, and the active substance is
percutaneously administered into the body, wherein the active
substance is a long-acting substance. No organic solvent is used to
prepare the base in the percutaneously absorbable preparations,
because the base consists of a water-soluble substance. More
specifically, the active substance remains active during the
manufacturing process, since the active substance held in the base
is kept from exposure to the organic solvent. As a result, the
active substance is highly efficiently absorbed through the skin.
Furthermore, no special treatment is needed to obtain the
sustained-release characteristics of the active substance, since a
long-acting substance is used as the active substance. Examples of
the long-acting substance include long-acting insulin and
polyethylene glycol complexed proteins.
[0025] Preferably, the polymer material is at least one material
selected from the group consisting of proteins, polysaccharides,
polyvinyl alcohols, carboxyvinyl polymers and sodium polyacrylic
acids.
[0026] The percutaneously absorbable preparations in this preferred
aspect is prepared at room temperature or at relatively low
temperature, because the base is made of protein etc. Therefore,
the active substance held on the base is kept from exposure to high
temperature during the manufacturing process. More specifically,
though the active substance is inherently unstable at high
temperature, it does not loss the activity during manufacturing
process. As a result, the active substance is highly efficiently
administered percutaneously into the body by the percutaneously
absorbable preparations.
[0027] Preferably, the protein is at least one material selected
from the group consisting of serum albumin, serum .alpha.-acid
glycoprotein and gelatin.
[0028] Preferably, the polysaccharide is at least one material
selected from the group consisting of glycogen, dextrin, dextran,
dextran sulfate, sodium chondroitin sulfate, hydroxy propyl
cellulose, alginic acid, agarose, chitin, chitosan, pullulan and
hyaluronic acid.
[0029] The percutaneously absorbable preparations in these
preferred aspects ensure hygienic safety, because the base is made
of pharmaceutical preparations whose safety is generally
acknowledged.
[0030] Preferably, the base contains an absorption rate controller
for controlling the absorption rate of the active substance.
[0031] Preferably, the absorption rate controller is an absorption
enhancer.
[0032] Preferably, the absorption enhancer is a surfactant.
[0033] In such preferred aspects, the dissolution rate and
permeability of the active substance is accelerated by the action
of surfactant even when the active substance has a low solubility
and a low permeability in the epidermis and dermis of the skin. As
a result, the active substance is effectively percutaneously
administered into the body.
[0034] Preferably, the base contains a thread-reducing agent,
thereby reducing the thread-forming property thereof.
[0035] Preferably, the thread-reducing agent is polyethylene glycol
or L-glutamic acid L-lysine.
[0036] According to the preferred aspects, the thread-forming
property of the base is reduced. Since the thread-forming property
of the base is well controlled, the preparations are smoothly
manufactured.
[0037] Preferably, the active substance is a drug.
[0038] The use of the drug-base percutaneously absorbable
preparations ensures that the active substance is effectively
administered percutaneously into the body for the therapy,
prophylaxis and diagnosis of disease.
[0039] Preferably, the drug falls in peptides, proteins, nucleic
acids, polysaccharides or vaccine.
[0040] According to the preferred aspect, percutaneously poorly
absorbable drugs like peptides, proteins, nucleic acids,
polysaccharides and vaccine are administered percutaneously into
the body.
[0041] Preferably, the base contains a stabilizer for stabilizing
the active substance.
[0042] In this case, the active substance held in the base is
stabilized by the action of the stabilizer. As a result, a possible
inactivation or any other inadequacy of the active substance is
eliminated. When the active substance is peptides or proteins, a
protease inhibitor and a nuclease inhibitor are desirably used for
peptides/proteins and nucleic acids, respectively.
[0043] Preferably, the preparations further include a
moisture-proof layer formed on the surface thereof.
[0044] Thus, the percutaneously absorbable preparation can have a
reduced hygroscopicity because of the existence of the
moisture-proof layer on its surface. As a result, the top of the
preparations is prevented from softening, and the percutaneously
absorbable preparations are inserted into the skin. The active
substance is administered exactly to a desired quantity.
[0045] Preferably, the preparations are constricted or have a
secant in part on the surface thereof.
[0046] The percutaneously absorbable preparations in this preferred
aspect are constricted or have a secant on the part or parts of
their surface, and are cut along the constricted portion or the
secant after the preparations are inserted into the skin. As a
result, the part or parts of the preparations, from the secant to
the top, are inserted into the skin and the active substance is
accurately dosed.
[0047] According to a fifth aspect of percutaneously absorbable
preparations of the present invention, the percutaneously
absorbable preparations are characterized in at least two of the
preparations of any one of the above-described aspects linked in
series.
[0048] According to this aspect, the linked series of preparations
are sequentially administered into the body through the skin.
[0049] According to an aspect of a sheet-like carrier of the
present invention, there is provided a sheet-like carrier for
holding at least one of the percutaneously absorbable preparations
on at least one of the surfaces thereof, wherein the preparations
held on the carrier are inserted into the skin by pushing the
carrier thereonto.
[0050] The present aspect is directed to a sheet-like carrier for
holding the percutaneously absorbable preparations, wherein at
least one of the percutaneously absorbable preparations except the
fifth aspect are held on the sheet-like carrier and the
percutaneously absorbable preparations are inserted into the skin
by pressing the sheet-like carrier onto the skin. As a result, the
percutaneously absorbable preparations held on the sheet-like
carrier are inserted into the skin. According to this aspect, the
percutaneously absorbable preparations are highly efficiently
administered.
[0051] According to an aspect of equipment of the present
invention, there is provided a piece of equipment for holding
percutaneously absorbable preparations including having a base of
water-soluble and biologically soluble polymer material, an active
substance held in the base, and having a slender, pointed shape,
such as a needle-like or filamentous shape, adapted for insertion
into skin to percutaneously administer the active substance into
the body, the equipment including a main body having a penetration
hole in and along which the preparations are moved.
[0052] According to another aspect of equipment of the present
invention, there is provided a piece of equipment for holding
percutaneously absorbable preparations, the equipment including a
main body having a penetration hole in and along which the
preparations are moved, wherein the preparations fall in any one of
the above-described aspects.
[0053] In the equipment in these aspects, the percutaneously
absorbable preparations move in and along the penetration hole, and
are inserted into the skin by pushing out the preparations from the
other end of the penetration hole. As a result, the preparations
are accurately and easily inserted into the skin.
[0054] Preferably, the penetration hole accommodates a spacer kept
in contact with the preparations held in the penetration hole, so
that the spacer moves in and along the penetration hole while being
kept in contact with the preparations.
[0055] When the preparations held in the penetration hole are
pushed to the skin, a pushing unit is inserted into the hole to
push it out from the other end of the hole. At the time when the
percutaneously absorbable preparations are completely inserted into
the skin, the pushing unit comes into contact with the skin.
However, a small amount of the body fluid may leak on the skin at a
spot where the preparations are inserted, and the body fluid may
adhere to the pushing unit. More specifically, when several pieces
of equipment are used one after another as if they are cartridges,
the patients are in danger of being infected through the body
fluid. The equipment in the preferred aspect has a spacer, which is
kept in contact with the percutaneously absorbable preparations in
the penetration hole. The spacer moves in and along the penetration
hole. By use of this equipment, the percutaneously absorbable
preparations are pushed via the spacer by a pushing unit. As a
result, the pushing unit does not come into contact with the skin
at the point when the preparations are completely inserted into the
skin. Therefore, by use of the equipment, there is no fear of
infection through the body fluid among the patients even if a
plurality of equipment are used one after another as if they are
cartridges.
[0056] Preferably, the main body includes a concave to which the
penetration hole is open.
[0057] Owing to the presence of the concave, the preparations are
easily released under the pushing urge. In addition, the concave
makes it easy to attach the pushing unit to the equipment.
[0058] Preferably, the concave includes female threads cut on the
inside wall thereof.
[0059] The equipment has female threads formed at its concave.
Therefore, the pushing unit having male threads is certainly
attached to the equipment.
[0060] Preferably, the main body is made of plastics.
[0061] The equipment is lightweight, and is convenient for use. In
addition, there is no fear of metallic allergy because it is not
made of metal.
ADVANTAGEOUS EFFECT OF THE INVENTION
[0062] By use of the percutaneously absorbable preparations
embodying the present invention, even if the active substance is a
percutaneously poorly absorbable drug, it is efficiently
administered percutaneously into the body.
[0063] By use of the sheet-like carrier embodying the present
invention, the percutaneously absorbable preparations are highly
efficiently administered.
[0064] By use of the equipment embodying the invention, the
needle-like or filamentous shape percutaneously absorbable
preparations are easily administered with high accuracy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] FIG. 1A is a perspective view showing an embodiment of the
needle-like percutaneously absorbable preparations, and FIG. 1B is
a perspective view which shows another embodiment of the
needle-like percutaneously absorbable preparations;
[0066] FIG. 2A is a perspective view showing a modified version of
the percutaneously absorbable preparations of FIG. 1A; FIG. 2B is a
perspective view showing another modified version of the
percutaneously absorbable preparations of FIG. 1A; and FIG. 2C is a
perspective view showing a modified version of the percutaneously
absorbable preparations of FIG. 1B.
[0067] FIG. 3 is a perspective view showing an embodiment of the
filamentous percutaneously absorbable preparations;
[0068] FIG. 4A is a perspective view showing an embodiment of the
percutaneously absorbable preparations having a secant in all
surroundings;
[0069] FIG. 4B is an enlarged sectional view of the part including
the secant of FIG. 4A; and FIG. 4C is a perspective view showing an
embodiment of the percutaneously absorbable preparations having a
secant on a part of the surroundings;
[0070] FIG. 5 is an enlarged sectional view of a constricted part
of the percutaneously absorbable preparations;
[0071] FIG. 6 is a perspective view showing an embodiment of the
percutaneously absorbable preparations in the fifth aspect;
[0072] FIG. 7A is a side view schematically showing the initial
stage of manufacturing process; FIG. 7B is a side view
schematically showing the midway stage thereof; and FIG. 7C is a
side view schematically showing the final stage thereof;
[0073] FIG. 8A is a side view schematically showing the initial
stage of manufacturing process; and FIG. 8B is a side view
schematically showing the final stage thereof;
[0074] FIG. 9 is an exploded perspective schematic view showing
another example of the process of manufacturing the percutaneously
absorbable preparations of the invention;
[0075] FIG. 10 is a perspective view showing an embodiment of a
sheet-like carrier for holding the percutaneously absorbable
preparations;
[0076] FIG. 11A is an exploded perspective view showing the first
embodiment of the equipment of the invention; and FIG. 11B is a
sectional perspective view showing the first embodiment
thereof;
[0077] FIG. 12A is a schematic sectional view showing the
pre-operation state of the equipment of FIG. 11; and FIG. 12B is a
schematic sectional view showing the post-operation state
thereof;
[0078] FIG. 13A is a sectional view showing the second embodiment
of the equipment of the invention; FIG. 13B is a sectional view
showing the third embodiment of the equipment of the invention;
[0079] FIG. 14 is a sectional view showing the fourth embodiment of
the equipment of the invention;
[0080] FIG. 15 is an exploded perspective view showing the
positional relations between the pushing unit and the equipment in
the fourth embodiment; and
[0081] FIG. 16A is a graph depicting the blood glucose level vs.
time profiles after the administration of the percutaneously
absorbable preparations in Example 20-1, 20-2 or 20-3; and FIG. 16
B is a graph depicting the blood glucose level vs. time profiles
after the administration of the percutaneously absorbable
preparations in Example 20-4, 20-5 or 21.
DESCRIPTION OF THE NUMERALS
[0082] 1, 1a-1q: percutaneously absorbable preparation [0083] 21:
percutaneously absorbable preparation [0084] 31: percutaneously
absorbable preparation [0085] 41, 41a-41d: percutaneously
absorbable preparation [0086] 51: percutaneously absorbable
preparation [0087] 61: percutaneously absorbable preparation [0088]
66: secant [0089] 67: constricted line [0090] 71: percutaneously
absorbable preparation [0091] 76a, 76b: secant [0092] 81:
percutaneously absorbable preparation [0093] 91: base [0094] 100:
sheet-like carrier for holding the percutaneously absorbable
preparation [0095] 102: supporting body [0096] 110: percutaneously
absorbable preparations holding equipment [0097] 111:
percutaneously absorbable preparation [0098] 112: main body [0099]
113: penetration hole [0100] 115: bead (spacer) [0101] 117: concave
[0102] 120: percutaneously absorbable preparations holding
equipment [0103] 121: percutaneously absorbable preparation [0104]
130: percutaneously absorbable preparations holding equipment
[0105] 131: percutaneously absorbable preparation [0106] 140:
percutaneously absorbable preparations holding equipment [0107]
147: concave
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0108] Hereinafter, preferred embodiments of the present invention
will be described in detail.
[0109] All the percutaneously absorbable preparations of the
present invention have a generally slender, pointed shape; herein,
this shape being referred to as "needle-like or filamentous shape".
Examples of "needle-like" and "filamentous" percutaneously
absorbable preparations according to the present invention are
illustrated by the accompanying drawings; FIGS. 1A and 1B show
examples of percutaneously absorbable preparations having a
needle-like or filamentous shape. FIG. 1A is a perspective view
showing an embodiment of the needle-like percutaneously absorbable
preparations. FIG. 1B is a perspective view which shows another
embodiment of the needle-like percutaneously absorbable
preparations. FIGS. 2A, 2B and 2C show modified versions of
percutaneously absorbable preparations of FIGS. 1A and 1B. FIG. 2A
is a perspective view showing a modified version of the
percutaneously absorbable preparations of FIG. 1A. FIG. 2B is a
perspective view showing another modified version of the
percutaneously absorbable preparations of FIG. 1A. FIG. 2C is a
perspective view showing a modified version of the percutaneously
absorbable preparations of FIG. 1B. FIG. 3 is a perspective view
showing an embodiment of the filamentous percutaneously absorbable
preparations.
[0110] Percutaneously absorbable preparation 1 shown in FIG. 1A has
a substantially conical shape, and has a substantially circular
pushing part 2, a surface 3 consisting of a curved surface, and a
pointed top 5. Percutaneously absorbable preparation 1 is inserted
into the skin by pushing the pushing part 2 under the condition
that the top 5 is kept in contact with the skin. The diameter D of
the pushing part 2 is in a range of about 0.1-500 .mu.m. The length
H of the percutaneously absorbable preparation 1 is in a range of
about 0.5-1500 .mu.m. The numerical values of 500 .mu.m which is
the maximum value of the diameter D and 1500 .mu.m which is the
maximum value of the length are bigger than the diameter and length
of the usual microneedles. More specifically, percutaneously
absorbable preparation 1 includes not only conventional
microneedles but also larger size microneedles. On the other hand,
percutaneously absorbable preparation 11 shown in FIG. 1B has a
substantially quadrilateral shape, and has a substantially square
pushing part 12, a surface 13 consisting of four planes, and a
pointed top 15. It is inserted into the skin by pushing the pushing
part 12 under the condition that the top 15 is in contact to the
skin. Percutaneously absorbable preparation 11 has the same size as
percutaneously absorbable preparation 1 shown in FIG. 1A. In the
percutaneously absorbable preparation 11 shown in FIG. 1B, though
the pushing part 12 is substantially square, another polygonal
shape is accepted. Percutaneously absorbable preparation 21 shown
in FIG. 2A is a modified version of the percutaneously absorbable
preparation 1 shown in FIG. 1A, and has a shape of a nail whose top
is sharpened. As the percutaneously absorbable preparation 1,
percutaneously absorbable preparation 21 is inserted into the skin
by pushing a pushing part 22 under the condition that a top 25 is
in contact with the skin. Percutaneously absorbable preparation 31
shown in FIG. 2B is another modified version of the percutaneously
absorbable preparation 1 and has a shape of the percutaneously
absorbable preparation 21 shown in FIG. 2A with a truncated cone
placed on the pushing part 2. Percutaneously absorbable preparation
31 is also inserted into the skin by pushing a pushing part 32
under the condition that a top 35 is kept in contact with the skin.
Percutaneously absorbable preparation 41 shown in FIG. 2C has a
shape of the percutaneously absorbable preparation 21 shown in FIG.
1B with a square pyramid placed on the pushing part 2.
Percutaneously absorbable preparation 41 is also inserted into the
skin by pushing a pushing part 42 under the condition that a top 45
is in contact with the skin. As mentioned above, percutaneously
absorbable preparations shown in FIGS. 1A-1B and 2A-2C are all
needle-like.
[0111] On the other hand, percutaneously absorbable preparation 51
shown in FIG. 3 is a filamentous solid preparation that has a shape
as if a circular cylinder is diagonally cut. Percutaneously
absorbable preparation 51 has a pushing part 52 having a
substantially circular shape, a surface 53 consisting of a curved
surface, and a pointed top 55. Percutaneously absorbable
preparation 51 is inserted into the skin by pushing the pushing
part 52 under the condition that the top 55 is in contact with the
skin. The percutaneously absorbable preparation 51 has the same
size as the percutaneously absorbable preparation 1 shown in FIG.
1A or the percutaneously absorbable preparation 11 as shown in FIG.
1B. The expression "Filamentous" is replaced with the expression
"Cylinder shape".
[0112] All the percutaneously absorbable preparations of the
present invention are those having a base of water-soluble and
biologically soluble polymer material, and an active substance held
in the base, including, having a slender, pointed shape, such as a
needle-like or filamentous shape, adapted for insertion into skin
to percutaneously administer the active substance into the body.
Percutaneously absorbable preparations of the present invention are
chiefly composed of five aspects. A first aspect relates to a
conventional preparation. Second, third and fourth aspects relate
to a sustained-release preparation. A fifth aspect relates to a
percutaneously absorbable preparation having at least two
percutaneously absorbable preparations linked in series.
[0113] In the first aspect of the percutaneously absorbable
preparations of this invention, the base consists of at least one
material selected from the group consisting of proteins,
polysaccharides, polyvinyl alcohols, carboxyvinyl polymers and
sodium polyacrylic acids. These polymer materials each allow a
stand-alone use or alternatively, a combination use with one or
more other kinds. The method to hold the active substance in the
base is not limited particularly, and various methods are applied.
For instance, the active substance is held by the base by
maintaining the active substance in the base as supramolecules. As
other examples, the active substance is held in the base by adding
the active substance to the dissolved base as suspension and
thereafter solidified.
[0114] In the second aspect of the percutaneously absorbable
preparations of this invention, a water-insoluble layer is formed
on the surface, and the active substance is released in a
sustained-release fashion. In a preferred embodiment of this
aspect, the water-insoluble layer is formed by a cross-linking
reaction. As the method to make a cross-linking reaction on the
surface, for example, cross-linking reaction by treating the
surface with glutaraldehyde is proposed. Precisely, percutaneously
absorbable preparations are soaked in glutaraldehyde solution. As
another method to make a water-insoluble layer on the surface
except a cross-linking reaction, the SiO thin film formation
reaction by the gas phase reaction used in the semiconductor field
is applied. As another example, the method to make the surface
insoluble by keeping under the condition of the high temperature
and high humidity is applicable when gelatin etc. is used as the
base, though this method is used in the field of capsule
technology. Still another method is to soak the percutaneously
absorbable preparations in a saturated calcium chloride solution.
On the other hand, as the method to hold active substance in the
base, for example, the same method as described in the first aspect
of the percutaneously absorbable preparations is applied.
[0115] In the third aspect of the percutaneously absorbable
preparations of this invention, the base contains a porous
compound. The active substance is held in the porous compound, and
is released in a sustained-release fashion. In a preferred
embodiment of this aspect, the porous material is at least one
material selected from the group consisting of calcium silicate,
aluminum silicate, magnesium silicate, anhydrous silicate, porous
calcium carbonate, porous calcium phosphate and porous silicon.
These porous materials each allow a stand-alone use or
alternatively, a combination use with one or more other kinds.
These porous materials are commercially obtainable, and may be used
without modification. For instance, calcium silicate includes
Florite (Trade name, Eisai Co., Ltd., Tokyo, Japan). Aluminum
silicate and magnesium silicate includes Neusilin (Registered
trademark, Fuji Chemical Industry Co., Ltd., Toyama, Japan).
Silicon dioxide includes Sylysia (Trade name, Fuji Silysia Co.,
Ltd., Aichi, Japan). Porous silicone includes BioSilicon (Trade
name, pSivida Inc.). In addition, porous calcium carbonate and
porous calcium phosphate are obtainable from National Institute for
Materials, Japan, for instance. In the fourth aspect of the
percutaneously absorbable preparations of this invention, the
active substance is a long-acting material and is released in a
sustained-release fashion. In a preferred embodiment of this
aspect, the long-acting substance is long-acting type insulin or
protein cross-linked with polyethylene glycol. Specific examples of
the long-acting insulin include middle-acting, long-acting and
ultra-long-acting insulins. Specific examples of the polyethylene
glycol cross-linked protein include PEG-modified proteins such as
PEG-interferon and PEG-erythropoietin.
[0116] In a preferred embodiment which is common to percutaneously
absorbable preparations of the above-mentioned second, third, and
fourth aspects, the base consists of at least one material selected
from the group consisting of proteins, polysaccharides, polyvinyl
alcohols, carboxyvinyl polymers and sodium polyacrylic acids, as
with the first aspect. These macromolecules each allow a
stand-alone use or alternatively, a combination use with one or
more other kinds.
[0117] Preferred embodiments common to percutaneously absorbable
preparations of the above-mentioned four aspects are described
below. In a preferred embodiment, the protein is at least one
material selected from the group consisting of serum albumin, serum
.alpha.-acid glycoprotein and gelatin. These proteins each allow a
stand-alone use or alternatively, a combination use with one or
more other kinds. Further, in a preferred embodiment, the
polysaccharide is at least one material selected from the group
consisting of glycogen, dextrin, dextran, dextran sulfate, sodium
chondroitin sulfate, hydroxy propyl cellulose, alginic acid,
agarose, chitin, chitosan, pullulan, and hyaluronic acid. These
polysaccharides each allow a stand-alone use or alternatively, a
combination use with one or more other kinds. With respect to the
molecular weight of the polysaccharides, for example, hyaluronic
acid with a molecular weight less than 1,200,000 are used, though
low molecular weight hyaluronic acid less than about 90,000 are
more preferable. For dextran, for instance, dextran of which
molecular weight is more than 50,000 is used. For dextran sulfate,
dextran sulfate of which molecular weight is about 500,000 is used.
For hydroxypropyl cellulose, low-substituted hydroxypropyl
cellulose is preferably used.
[0118] In a preferred embodiment, the base contains an absorption
rate controller for controlling the absorption rate of the active
substance. In a further preferred embodiment, the absorption rate
controller is an absorption enhancer. In a still further preferred
embodiment, the absorption enhancer is a surfactant. Examples of
the absorption enhancer include fatty acids such as caprylic acid,
capric acid and its derivatives, N-8-(2-hydroxybenzoyl)amino
caprylic acid (SNAC), and sodium N-8-(2-hydroxybenzoyl)amino
decanate (SNAD); glycyrrhizin; glycyrrhizinic acid; amino acid
enamine derivatives such as ethyl acetoacetate ethylenamine
derivatives of phenylglycine; sodium salicylate and its
derivatives; mixed micelles such as mixed micelles of mono-olein
and sodium glycocholate, and mixed micelles of mono-olein and
sodium taurocholates; N-acylcollagen peptide; sodium acylamino
acid; Plectranthus japonicus saponin; bile acids; chelate compounds
such as EDTA; organic acids such as citric acids and tartaric
acids. However, the absorption enhancer used in this embodiment is
not limited particularly to these materials.
[0119] Surfactant as an absorption enhancer is used to increase the
bioavailability and pharmacological activity of the active
substance by accelerating the dissolution rate of the active
substance with low solubility in the surface and the dermis of the
skin and by enhancing the absorption of the active substance having
low membrane permeability through the skin. Examples of the
surfactant include glycerin fatty acid esters, commercially
available as "Ryoto (registered trademark) Polyglyester" supplied
by Mitsubishikagaku Foods Co. Ltd., such as decaglycerine lauric
acid esters L-7D and L-10D; decaglycerine myristic acid ester
M-10D; decaglycerine stearic acid esters SWA-10D, SWA-15D, SWA-20D,
S-24D and S-28D; decaglycerine oleic acid esters O-15D and O-50D;
decaglycerine behenic acid esters B-70D and B-100D; decaglycerine
erucic acid esters ER-30D and ER-60D; decaglecerine mixed fatty
acid ester LOP-120DP; polyglycerine stearic acid esters DS13W, DS3,
HS11, HS9, TS4 and TS2; polyglycerine lauric acid ester DL15; and
polyglycerine oleic acid ester DO13.
[0120] Further, examples of the surfactant include stearoyl calcium
lactate, sorbitan fatty acid ester, and propylene glycol fatty acid
ester. Further, the examples include fatty acid sugar esters,
commercially available as "Ryoto (registered trademark) Sugarester"
supplied by Mitsubishikagaku Foods Co. Ltd., such as S-1670,
S-1570, S-1170, P-1570, P-1670, M-1695, O-1570, OWA 1570, and
L-1695. Further, the examples include DK esters F-160, F-140, and
F-110 (Dai-ichi Kogyo Seiyaku Co., Ltd.). Further, the examples
include polysorbate 80, monooleic acid, polyethylene glycol
monooleate, polyethylene glycol monostearate, and middle chain
fatty acid triglycerides. Further, the examples include the
saturated fatty acids (C.sub 6 to C.sub 12) such as caproic acid,
caprylic acid, capric acid, lauric acid, and lecithin.
[0121] Still further, liquid, semi-solid or solid surfactants
except the above mentioned surfactants are used in this embodiment.
These surfactants are described separately with three categories,
namely, non-ionic surfactants, hydrophilic surfactants and ionic
surfactants.
[0122] (a) Nonionic Surfactant
alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl
macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene
alkylphenols; polyethylene glycol fatty acids esters; polyethylene
glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty
acid esters; polyoxyethylene-polyoxypropylene block copolymers;
polyglycerol fatty acid esters; polyoxyethylene glycerides;
polyoxyethylene sterols; polyoxyethylene vegetable oils;
polyoxyethylene hydrogenated vegetable oils; reaction mixtures of
polyols with at least one selected from the group consisting of
fatty acids, glycerides, vegetable oils, hydrogenated vegetable
oils, and sterols; sugar esters, sugar ethers; sucroglycerides; and
mixtures thereof.
[0123] (b) Hydrophilic Surfactants
PEG-10 laurate; PEG-12 laurate; PEG-20 laurate; PEG-32 laurate;
PEG-32 dilaurate; PEG-12 oleate; PEG-15 oleate; PEG-20 oleate;
PEG-20 dioleate; PEG-32 oleate; PEG-200 oleate; PEG-400 oleate;
PEG-15 stearate; PEG-32 distearate; PEG-40 stearate; PEG-100
stearate; PEG-20 dilaurate; PEG-25 glyceryl trioleate; PEG-32
dioleate; PEG-20 glyceryl laurate; PEG-30 glyceryl laurate; PEG-20
glyceryl stearate; PEG-20 glyceryl oleate; PEG-30 glyceryl oleate;
PEG-30 glyceryl laurate; PEG-40 glyceryl laurate; PEG-40 palm
kernel oil; PEG-50 hydrogenated castor oil; PEG-40 castor oil;
PEG-35 castor oil; PEG-60 castor oil; PEG-40 hydrogenated castor
oil; PEG-60 hydrogenated castor oil; PEG-60 corn oil; PEG-6
caprate/caprylate glycerides; PEG-8 caprate/caprylate glycerides;
polyglyceryl-10 laurate; PEG-30 cholesterol; PEG-25 phyto sterol;
PEG-30 soya sterol; PEG-20 trioleate; PEG-40 sorbitan oleate;
PEG-80 sorbitan laurate; polysorbate 20; polysorbate 80; POE-9
lauryl ether; POE-23 lauryl ether; POE-10 oleyl ether; POE-20 oleyl
ether; POE-20 stearyl ether; tocopheryl PEG-100 succinate; PEG-24
cholesterol; polyglyceryl-10 oleate; Tween 40; Tween 60; sucrose
monostearate; sucrose monolaurate; sucrose monopalmitate; PEG
10-100 nonyl phenol series; PEG 15-100 octyl phenol series; and
poloxamer; and mixtures thereof.
[0124] (c) Ionic Surfactants
alkyl ammonium salts; bile acids and salts; fusidic acid; fatty
acid conjugates of amino acids, oligopeptides, or polypeptides;
glyceride esters of polypeptides; acyl lactylates; mono- and
diacetylated tartaric acid esters of mono- and diglycerides;
succinylated monoglycerides; citric acid esters of mono- and
diglycerides; alginate salts; propylene glycol alginate; lecithins;
hydrogenated lecithins; lysolecithin; hydrogenated lysolecithins;
lysophospholipids; phospholipids; salts of alkylsulfates; and salts
of fatty acids.
[0125] Typical examples of the ionic surfactants include the
following: phosphatidylcholine; phosphatidylethanolamine;
phosphatidylglycerol; phosphatidic acid; phosphatidylserine;
lysophosphatidylcholine; lysophosphatidylethanolamine;
lysophosphatidylglycerol; lysophosphatidic acid;
lysophosphatidylserine; PEG-phosphatidylethanolamine;
PVP-phosphatidylethanolamine; lactylic esters of fatty acids;
stearoyl-2-lactylate; succinylated monoglycerides;
mono/diacetylated tartaric acid esters of mono/diglycerides; citric
acid esters of mono/diglycerides; cholate; taurocholate;
glycocholate; deoxycholate; taurodeoxycholate; chenodeoxycholate;
glycodeoxycholate; glycochenodeoxycholate; taurochenodeoxycholate;
ursodeoxycholate; lithocholate; tauroursodeoxycholate;
glycoursodeoxycholate; cholylsarcosine; N-methyl taurocholate;
caproate; caprylate; caprate; laurate; myristate; palmitate;
oleate; ricinoleate; linoleate; linolenate; stearate; lauryl
sulfate; teracecyl sulfate; docusate; lauroyl carnitines; palmitoyl
carnitines; myristoyl carnitines; and salts thereof; and mixtures
of them including salts.
[0126] These surfactants also have a function of plasticizer. For
instance, both absorption enhancing effect and stabilizing effect
on the physical strength of percutaneously absorbable preparations
are obtained by formulating polysorbate 80 into the base consisting
of serum albumin.
[0127] In a preferred embodiment, the base contains a
thread-reducing agent, thereby reducing the thread-forming property
thereof. It has an advantage in manufacturing, because the
thread-forming property of the base is well controlled in this
embodiment. Examples of the thread-reducing agent include
polyethylene glycol and L-glutamic acid L-lysine.
[0128] There is no limitation on the active substance in
percutaneously absorbable preparations of this invention. Examples
of the active substances include drugs, physiologically active
substances, cosmetics and nutrients. When drugs are employed as an
active substance, especially poorly absorbable drugs through
percutaneous route are good candidate. Examples of category of the
percutaneously poorly absorbable drugs include peptides, proteins,
nucleic acids, polysaccharides, other compounds of which molecular
weight is larger than 1,000, and vaccines. Examples of peptides and
proteins include physiologically active peptide/proteins such as
insulin, calcitonin, erythropoietin (EPO), interferon, various
interleukins, granulocyte colony-stimulating factors (G-CSF),
vasopressin, desmopressin, urokinase, growth hormone, parathyroid
hormone and grehelin. Examples of nucleic acids include vectors for
gene therapy, anti-sense DNA, anti-sense RNA, and siRNA. Further,
examples of vaccines include vaccines containing microorganism such
as attenuated vaccines and inactivated vaccines, peptide vaccines,
and nucleic acid vaccines such as DNA vaccines. Examples of
polysaccharides include heparin and low molecular weight
heparin.
[0129] Although there is no limitation in the content of the active
substance in the percutaneously absorbable preparation of this
invention, the content is generally 0.01-50 w/w %.
[0130] In a preferred embodiment, the base contains a stabilizer
for stabilizing the active substance. Especially, when peptides or
proteins are employed as an active substance, it is preferable to
contain protease inhibitor as a stabilizer. Examples of the
protease inhibitors include aprotinin and trypsin inhibitor.
Further, when nucleic acids are employed as an active substance, it
is preferable to contain nuclease inhibitor as a stabilizer.
[0131] In a further preferred embodiment, a moisture-proof layer is
formed on the surface of the percutaneously absorbable
preparations. For example, the moisture-proof layer is prepared by
coating the surface with polymer solution like polyethylene glycol
(PEG), polyvinylpyrolidone and polylactic acid, etc.
[0132] In all embodiments of the above-mentioned percutaneously
absorbable preparations, the surface is constricted or has a
secant. More specifically, the dose of the administered active
substance is made accurate by splitting along the constricted line
or the secant after inserting the percutaneously absorbable
preparations into the skin. The constricted line or the secant may
be provided to all or a part of surroundings of the preparation.
FIGS. 4A, 4B and 4C show embodiments of the percutaneously
absorbable preparations having a secant. FIG. 4A is a perspective
view showing an embodiment of the percutaneously absorbable
preparations having a secant in all surroundings. FIG. 4B is an
enlarged sectional view of the part including the secant of FIG.
4A. FIG. 4C is a perspective view showing an embodiment of the
percutaneously absorbable preparations having a secant on a part of
the surroundings. Percutaneously absorbable preparation 61 shown in
FIG. 4A is prepared by providing preparation 1 shown in FIG. 1A
with a secant. A secant 66 is made on a surface 63 in all
surroundings. As shown in FIG. 4B, the secant 66 has a shape like a
square groove. On the other hand, percutaneously absorbable
preparation 71 as shown in FIG. 4C is prepared by providing
preparation 1 shown in FIG. 1A with two secants. More specifically,
secants 76a and 76b are made on mutually opposed portions on a
surface 73. The shape of the secants 76a and 76b is the same as the
secant 61 shown in FIG. 4B. The secants 76a and 76b in FIG. 4A,
FIG. 4B and FIG. 4C are drawn in an exaggerated manner by the size
and the size may be different from an actual size.
[0133] In the percutaneously absorbable preparation 61 shown in
FIG. 4A, an example of providing a constricted line instead of the
secant 66 is shown in FIG. 5. FIG. 5 is an enlarged sectional view
of a constricted part of the percutaneously absorbable
preparations. As shown in FIG. 5, a constricted line 67 has a shape
like a V-groove. Of course, as with the percutaneously absorbable
preparation 61 shown in FIG. 4C, the constricted line 67 of FIG. 5
may be provided partially on the surface 63 instead of all
surroundings on the surface 63. The constricted line 67 in FIG. 5
is drawn in an exaggerated manner by the size and the size may be
different from an actual size.
[0134] According to the fifth aspect of the invention,
percutaneously absorbable preparations include at least two of
percutaneously absorbable preparations of the first, second, third
or fourth embodiment, wherein the preparations are linked in
series. FIG. 6 is a perspective view showing an embodiment of the
percutaneously absorbable preparations in the fifth aspect. In the
percutaneously absorbable preparation 81 shown in FIG. 6, several
percutaneously absorbable preparations shown in FIG. 2C are linked.
More specifically, in the percutaneously absorbable preparation 81
shown in FIG. 6, four percutaneously absorbable preparations
41a-41d are linked in series, resulting in providing four connected
parts 48a-48c. When the percutaneously absorbable preparation 81 is
used, the part of the percutaneously absorbable preparation 41a is
first inserted into the skin, and then cut at the connected part
48a. Next, the part of the percutaneously absorbable preparation
41b is inserted into another part on the skin, and then cut at the
connected part 48b. Similarly, the steps of "insertion into the
skin" and "cut at a connected part" are repeated. The four
percutaneously absorbable preparations 41a-41d are continuously
administered according to the percutaneously absorbable preparation
81 in this embodiment.
[0135] Manufacturing methods of the percutaneously absorbable
preparations of this invention will be described. Manufacturing
methods of the percutaneously absorbable preparations of this
invention are not limited particularly, and various methods are
applicable. In an example, a plate and a stick are used. FIG. 7
schematically shows the manufacturing process of the invented
percutaneously absorbable preparations. FIG. 7A is a side view
schematically showing the initial stage of manufacturing process.
FIG. 7B is a side view schematically showing the midway stage
thereof. FIG. 7C is a side view schematically showing the final
stage thereof. First of all, a base 91 that contains the active
substance is put on a plate 92 that consists of fluorocarbon resin
etc. In this case, it is preferable that the base consists of a
thread-forming material so as to be a paste after dissolved with
water. Next, the top of a glass stick 93 is in contact to the base
91 containing an active substance (FIG. 7A). The glass stick 93 is
lifted at once, and the base 91 containing an active substance and
adhering to the top of the glass stick 93 is enlarged (FIG. 7B). In
addition, the glass stick 93 is lifted, and the base 91 containing
an active substance is molded in a needle-like or filamentous shape
(FIG. 7C). Afterwards, percutaneously absorbable preparation 1
having substantially the same shape as a truncated cone is
manufactured by drying and hardening the needle-like or filamentous
shaped base 91 that contains an active substance. At this time, a
glass stick of which diameter is less than 5 mm is used, for
instance. Moreover, it does not limit to the glass stick, and a
water-insoluble stick made of polypropylenes etc. is
acceptable.
[0136] Although FIGS. 7A-7C show an example of the manufacturing
method of one percutaneously absorbable preparation, several
percutaneously absorbable preparations are made by the same
principle. An example of such a manufacturing method is shown in
FIGS. 8A and 8B. These figures schematically show another method to
make percutaneously absorbable preparations of the invention. FIG.
8A is a side view schematically showing the initial stage of
manufacturing process. FIG. 8B is a side view schematically showing
the final stage thereof. As shown in FIG. 8A, a comb 95 having two
or more projections instead of a stick is used in this example.
Then, five percutaneously absorbable preparations 1a-1e are made as
shown in FIG. 8B through the same processes shown in FIGS. 7A-7C.
Of course, it is also possible to manufacture more percutaneously
absorbable preparations by increasing the number of projections of
the comb 95.
[0137] A method using a mold is also applicable as another
manufacturing method of percutaneously absorbable preparations of
this invention. An example of the manufacturing process of the
percutaneously absorbable preparations using mold is shown in FIG.
9. FIG. 9 is an exploded perspective schematic view showing another
example of the process of manufacturing the percutaneously
absorbable preparations of the invention. As shown in FIG. 9, a
mold 97 is prepared by making conic holes 98a, 98b, and 98c in
front of the plate 92 that consists of fluorocarbon resin etc. The
base containing an active substance is filled into these holes 98a,
98b, and 98c, and is removed after drying or solidification. As a
result, needle-like or filamentous shape percutaneously absorbable
preparations 1f, 1g and 1h are manufactured. If the base containing
an active substance is a paste, it may be dried or solidified after
removed from the holes. The material of the plate 92 is not limited
to be fluorocarbon resin. For example, a plate made of silicon
resin or ABS resins are acceptable.
[0138] Methods to make a constricted line or a secant on the
percutaneously absorbable preparations of this invention are not
limited particularly, and various methods are used. When a mold is
used, a mold having a shape that can provide a constricted line or
a secant is employed. When a plate and a stick are used, the
constricted line or the secant is made, for instance, by pressing a
desired point before drying or solidification process. Moreover,
the constricted line or the secant is also made by shaving the
desired point after drying or solidification process.
[0139] One aspect of a sheet-like carrier of the invention is a
sheet-like carrier for holding at least one of the percutaneously
absorbable preparations except the fifth aspect on at least one of
the surfaces thereof, wherein the preparations held on the carrier
are inserted into the skin by pushing the carrier thereonto. An
embodiment of the sheet-like carrier of this aspect is shown in
FIG. 10. FIG. 10 is a perspective view showing an embodiment of a
sheet-like carrier for holding the percutaneously absorbable
preparations. More specifically, a percutaneously absorbable
preparations holding sheet-like carrier 100 in this embodiment
consists of a sheet-like supporting body 102 and nine
percutaneously absorbable preparations 1i-1q, and the nine
percutaneously absorbable preparations 1i-1q are held on the one
side of the supporting body 102. The nine percutaneously absorbable
preparations 1i-1q are inserted into the skin by pushing the
sheet-like carrier 100 onto the skin. After the sheet-like carrier
100 is pushed onto the skin, the supporting body 102 may be kept
contact to the skin or only the supporting body 102 is removed from
the skin. Although the sheet-like carrier 100 which holds nine
percutaneously absorbable preparations 1i-1q is shown in FIG. 10, a
sheet-like carrier of the present invention has no limitation on
the number of percutaneously absorbable preparations, i.e. is
allowed to hold one preparation only or, on the other hand, to hold
more than 10 preparations. As the supporting body 102, conventional
supporting bodies for use as a patch are used.
[0140] One aspect of equipment of the invention is equipment for
holding percutaneously absorbable preparations including having a
base of water-soluble and biologically soluble polymer material, an
active substance held in the base, and having a slender, pointed
shape, such as a needle-like or filamentous shape, adapted for
insertion into skin to percutaneously administer the active
substance into the body, the equipment including a main body having
a penetration hole in and along which the preparations are moved.
Embodiments of the equipment in this aspect are described with
reference to FIGS. 11A-11B, 12A-12B and 13. FIGS. 11A and 11B show
the first embodiment of the equipment of the invention. FIG. 11A is
an exploded perspective view showing the first embodiment of the
equipment of the invention. FIG. 11B is a sectional perspective
view showing the first embodiment thereof. FIGS. 12A and 12 B
schematically show the pre- and post-operation states of the
equipment of FIG. 11. FIG. 12A is a schematic sectional view
showing the pre-operation state of the equipment of FIG. 11. FIG.
12B is a schematic sectional view showing the post-operation state
thereof. FIGS. 13A and 13B show other embodiments of the equipment
of the invention. FIG. 13A is a sectional view showing the second
embodiment of the equipment of the invention. FIG. 13B is a
sectional view showing the third embodiment of the equipment of the
invention. FIG. 14 is a sectional view showing the fourth
embodiment of the equipment of the invention. FIG. 15 is an
exploded perspective view showing the positional relations between
the pushing unit and the equipment in the fourth embodiment.
[0141] As shown in FIG. 11A, percutaneously absorbable preparations
holding equipment 110 is composed of a main body 112 made of
plastic, a bead 115 (spacer) and a percutaneously absorbable
preparation 111. A penetration hole 113, which leads up and down,
is installed in the main body 112, and the bead 115 and the
percutaneously absorbable preparation 111 are held in the
penetration hole 113. The bead 115 and the percutaneously
absorbable preparation 111 move in and along the penetration hole
113. In addition, the bead 115 comes in contact with the
percutaneously absorbable preparation 111. The outer shape of the
main body 112 is like a truncated cone. Its large diameter is about
20 mm, its small diameter is about 10 mm, and its height is about
20 mm. Percutaneously absorbable preparation 111 is a preparation
of either of the above described first to fourth embodiments.
Percutaneously absorbable preparation 111 has the similar shape as
percutaneously absorbable preparation 21 shown in FIG. 2A. Its
diameter is about 0.2 mm, and its length is about 1.0 mm. The bead
115 is a spheroidal member, and its diameter is almost the same as
the diameter of the percutaneously absorbable preparation 111. The
bead 115 is made of silicon, but glass, resin and metal etc. are
also acceptable. In addition, the percutaneously absorbable
preparations holding equipment 110 has a skin contact surface 116
on the small diameter side. The skin contact surface 116 comes in
contact with the skin when the percutaneously absorbable
preparation 111 is used. Moreover, as shown in FIG. 11B, the main
body 112 has a concave 117 to which an end of the penetration hole
113 is open. The concave 117 is made so that a pushing unit for
pushing out the percutaneously absorbable preparation 111 via the
bead 115 is smoothly installed. In FIGS. 11A and 11B, to facilitate
the understanding, the size of the percutaneously absorbable
preparation 111 and the penetration hole 113 is drawn as an
enlarged manner.
[0142] As shown in FIG. 12A, the bead 115 and the percutaneously
absorbable preparation 111 are stored in penetration hole 113 in
the pre-operation state of the equipment 110. When it is used, one
side of the bead 115 is pushed from the side of the concave 117 of
the percutaneously absorbable preparations holding equipment 110.
The bead 115 comes in contact with the percutaneously absorbable
preparation 111, and then, the percutaneously absorbable
preparation 111 is pushed via the bead 115. In this embodiment, one
side of the bead 115 is pushed with a wire 118. The wire 118 is
made of stainless steel and has almost the same diameter as the
bead 115. As shown in FIG. 12B, the percutaneously absorbable
preparation 111 is completely pushed out by the wire 118 via the
bead 115 and is inserted into the skin 119. At this time, the wire
118 does not come in contact with the skin 119, because it works
via the bead 115. More specifically, the wire 118 is not polluted
by the body fluid secreted from the skin 119. In FIGS. 12A and 12B,
to facilitate the understanding, the sizes of the percutaneously
absorbable preparations 111, the penetration hole 113, the bead
115, and the wire 118 are drawn as an enlarged manner.
[0143] In the percutaneously absorbable preparations holding
equipment 110, another shape of the held percutaneously absorbable
preparations is acceptable. Percutaneously absorbable preparations
holding equipment 120 as shown in FIG. 13A holds a percutaneously
absorbable preparation 121 having a filamentous shape. The
percutaneously absorbable preparation 121 has almost the similar
shape as the percutaneously absorbable preparation 51 of FIG. 3,
and the size is almost the same as that of the percutaneously
absorbable preparation 111. On the other hand, percutaneously
absorbable preparations holding equipment 130 shown in FIG. 13B
holds a percutaneously absorbable preparation 131 having two
percutaneously absorbable preparations 41, shown in FIG. 2C, linked
in series. According to the percutaneously absorbable preparations
holding equipment 130, half of the percutaneously absorbable
preparation 131 is repeatedly administered at two times.
[0144] Female threads are formed in a concave 147 of percutaneously
absorbable preparations holding equipment 140 shown in FIG. 14. The
percutaneously absorbable preparations holding equipment 140 in
this embodiment is used by installing it to a pushing unit 141
shown in FIG. 15. The pushing unit 141 has the wire 118, and the
wire 118 moves at a constant distance by pushing a knock part 143.
Moreover, the pushing unit 141 has a convex part 142 that engages
with the concave 147 of the percutaneously absorbable preparations
holding equipment 140. Male threads are made in just fit to the
female threads formed in the concave 147 in the convex part 142. As
the pushing unit 141, for example, a mechanical pencil for writing
is applicable. More specifically, a mechanical pencil becomes
useful as the pushing unit 141 by using the wire 118 instead of an
extra lead, wherein the diameter of the wire 118 is the same as
that of the extra lead. Moreover, the pushing unit 141 can be made
by using the mechanism of a knock-type ballpoint pen. In FIGS. 13A,
13B, 14 and 15, to facilitate the understanding, the sizes of the
percutaneously absorbable preparations 111, 121, 131, bead 115, and
the wire 118 are drawn as an enlarged manner.
[0145] As mentioned above, the percutaneously absorbable
preparations holding equipments 110, 120, 130 and 140 are mainly
used as if it were a cartridge of percutaneously absorbable
preparations. A required number of percutaneously absorbable
preparations holding equipments 110, 120, 130 and 140 are used by
breaking the package when the equipments are packaged piece by
piece. Consequently, they are kept hygienic.
[0146] The following provides a more detailed explanation of the
present invention through its examples, though this invention is
not limited with these examples.
EXAMPLE 1
[0147] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing interferon (active substance) held in a base consisting
of human serum albumin.
[0148] About 0.2 mL of distilled water was added to 150 mg of human
serum albumin (Sigma) to be dissolved. The solution was mixed well
to give a base paste consisting of human serum albumin. To this
base paste, .mu.L of interferon alpha injection solution
"Sumiferon" (Trademark, 6,000,000 units/mL, Sumitomo
pharmaceuticals), corresponding to 60,000 IU, was added and well
mixed so that interferon was held in the base paste. To the base
paste holding interferon, a top of a glass stick of which diameter
was about 3 mm was attached. Thereafter, the top was gradually
pulled apart so that the base paste attaching to the top has a
needle-like or filamentous shape. The needle-like or filamentous
base paste was solidified by drying at low temperature to give a
percutaneously absorbable preparation having a needle-like or
filamentous shape.
[0149] Mice, about 30 g body weight, were fixed on an
operating-table after the abdominal hair was shaved under
anesthetized with pentobarbital. At this point, about 0.25 mL blood
sample was at first collected from the jugular vein. Next, the
percutaneously absorbable preparation made in this example was
inserted into the shaved abdominal skin of mice, and interferon was
administered percutaneously, wherein the dose of interferon was
10,000 IU/kg. Blood samples were collected from the jugular vein
for 4 hr after administration. Serum sample was prepared from the
obtained each blood sample, and interferon concentration of each
serum sample was measured with ELISA. All data were calculated as
the mean +/-standard deviation (SD), wherein each group consists of
three to four mice. The results are shown in Table 1. "ND" shows
the concentration below the detection limit (as the same as the
following tables). As a result, interferon concentration started to
increase at 1 hr after administration and showed its maximum
concentration (22.9+/-7.9 IU/mL) at 3 hr after administration.
Therefore, it was shown that interferon was administered
percutaneously with the percutaneously absorbable preparation of
this example.
TABLE-US-00001 TABLE 1 Elapsed time after administration (hr)
before admin- istration 1 2 3 4 Interferon ND 5.8 .+-. 3.8 19.3
.+-. 8.5 22.9 .+-. 7.9 17.7 .+-. 3.4 concentra- tion (IU/mL)
EXAMPLE 2
[0150] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing interferon (active substance) held in a base consisting
of bovine serum .alpha.-acid glycoprotein (AAG).
[0151] About 50 .mu.L of distilled water was added to 50 mg of
bovine AAG (Sigma) to be dissolved. The solution was mixed well and
water was evaporated to give a base paste consisting of AAG. To
this base paste, 10 .mu.L of interferon alpha injection solution
"Sumiferon" (Trademark, 6,000,000 units/mL, Sumitomo
pharmaceuticals), corresponding to 60,000 IU, was added and well
mixed so that interferon was held in the base paste. A
Percutaneously absorbable preparation having a needle-like or
filamentous shape was made with a glass stick in the same way as
Example 1.
EXAMPLE 3
[0152] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing FITC-labeled albumin (active substance) held in a base
consisting of human serum albumin. FITC-labeled albumin was used as
a model of vaccine.
[0153] FITC-labeled albumin was prepared by labeling human serum
albumin with fluorescein isothiocyanate (FITC). On the other hand,
about 0.2 mL of distilled water was added to 130 mg of human serum
albumin (Sigma) to be dissolved. The solution was mixed well to
give a base paste consisting of human serum albumin. To this base
paste, 20 mg of FITC-labeled albumin was added and well mixed, so
that FITC-labeled albumin was held in the base paste. To the base
paste holding FITC-labeled albumin, a top of a polypropylene stick
of which diameter was about 2 mm was attached. Thereafter, the top
was gradually pulled apart so that the base paste attaching to the
top has a needle-like or filamentous shape. The needle-like or
filamentous base paste was solidified by drying at low temperature
to give a percutaneously absorbable preparation having a
needle-like or filamentous shape.
[0154] Mice, about 30 g body weight, were fixed on an
operating-table after the abdominal hair was shaved under
anesthetized with pentobarbital. At this point, about 0.25 mL blood
was at first collected from the jugular vein. Next, five
percutaneously absorbable preparations prepared in this example
were inserted into the mice abdominal skin, and FITC-labeled
albumin was administered percutaneously. Whole blood was removed in
the next day and serum sample was prepared from the resulting
blood. Each serum sample was diluted at 20 times with distilled
water and the fluorescent intensity was measured with
spectrofluorometer with the excitation wavelength of 490 nm and
emission one of 510 nm. As a result, the serum sample obtained
after administration showed 20 times stronger fluorescent intensity
than that obtained before administration. From these results, it
was shown that FITC-labeled albumin as a model vaccine was
administered percutaneously.
EXAMPLE 4
[0155] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in a base consisting of
sodium chondroitin sulfate C.
[0156] About 0.1 mL of distilled water was added to 200 mg of
sodium chondroitin sulfate C (Nacalai Tesque) to be dissolved. The
solution was mixed well under warm to give a base paste consisting
of sodium chondroitin sulfate C. After cooled to the room
temperature, 10 .mu.L of sodium insulin solution (100 mg/mL,
private processed product) was added to this base paste and well
mixed so that insulin was held in the base paste. To the paste base
holding insulin, a top of a polypropylene stick of which diameter
was about 3 mm was attached. Thereafter, the top was gradually
pulled apart so that the base paste attaching to the top has a
needle-like or filamentous shape. In addition, a secant was made on
the surface of the needle-like or filamentous base paste with a
wire of which diameter was 20 .mu.m. The needle-like or filamentous
base paste with the secant was solidified by drying at low
temperature to give a percutaneously absorbable preparation having
a needle-like or filamentous shape.
[0157] The percutaneously absorbable preparation made in this
example was evaluated by means of hypoglycemic effect in mice.
Mice, about 30 g body weight, were anesthetized by an injection of
pentobarbital and were fixed on the operating-table after the hair
of the abdomen was shaved. At this point, about 0.25 mL blood was
at first collected from the jugular vein. Next, five percutaneously
absorbable preparations (corresponding to 1.0 IU/kg) made in this
example was inserted into the shaved abdomen, and insulin was
administered percutaneously. Blood samples were collected from the
jugular vein for 3 hr after administration. Serum samples were
obtained from the obtained blood samples and glucose content in
each serum sample was measured using glucose assay kit (Glucose C
II-Test kit, Wako Pure Chemical Industries). Each glucose level was
shown as a relative value to the pre-dose level, 100%. All data
were calculated as the mean +/-standard deviation (SD), where each
group consisting of three to four mice. The results are shown in
Table 2. As a result, serum glucose level showed its minimum value
within 1 hr after administration, and the effect of insulin was
confirmed. From these results, it was shown that insulin was
administered percutaneously by the percutaneously absorbable
preparation of this example.
TABLE-US-00002 TABLE 2 Elapsed time after administration (hr)
before administration 1 2 3 4 Glucose 100 28 .+-. 8 35 .+-. 11 62
.+-. 9 77 .+-. 8 level (%)
EXAMPLE 5
[0158] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in a base consisting of
dextrin.
[0159] About 1 mL of distilled water was added to 2 g of dextrin
(Wako Pure Chemical Industries) to be dissolved. The solution was
mixed well with motor and pestle to give a base paste consisting of
dextrin. Ten .mu.L of sodium insulin solution (100 mg/mL, private
processed product) was added to 100 mg of this base paste and well
mixed so that insulin was held in the base paste. To the base paste
holding insulin, a top of a glass stick of which diameter was about
3 mm was attached. Thereafter, the top was gradually pulled apart
so that the base paste attaching to the top has a needle-like or
filamentous shape. In addition, a secant was made on the surface of
the needle-like or filamentous base paste with a wire of which
diameter was 20 .mu.m. The needle-like or filamentous base paste
with the secant was solidified by drying at low temperature to give
a percutaneously absorbable preparation having a needle-like or
filamentous shape.
[0160] Animal experiments using mice were performed in the same way
as Example 4. Table 3 shows the result. As a result, serum glucose
level showed its minimum value within 1 hr after administration,
and the effect of insulin was confirmed. From these results, it was
shown that insulin was administered percutaneously by the
percutaneously absorbable preparation of this example.
TABLE-US-00003 TABLE 3 Elapsed time after administration (hr)
before administration 1 2 3 4 Glucose level 100 21 .+-. 6 30 .+-. 7
56 .+-. 8 63 .+-. 7 (%)
EXAMPLE 6
[0161] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing erythropoietin (active substance) held in a base
consisting of hydroxypropyl cellulose.
[0162] About 1 mL of distilled water was added to 2 g of
hydroxypropyl cellulose (L-HPC, Nippon Soda) to be dissolved. The
solution was mixed well with motor and pestle to give a base paste
consisting of hydroxypropyl cellulose. Ten .mu.L of erythropoietin
EPO injection "ESPO" (Trademark, 24,000 IU/mL, Kirin Breweries) was
added to 100 mg of this base paste and well mixed so that
erythropoietin was held in the base paste. To the base paste
holding erythropoietin, a top of a glass stick of which diameter
was about 3 mm was attached. Thereafter, the top was gradually
pulled apart so that the base paste attaching to the top has a
needle-like or filamentous shape. The needle-like or filamentous
base paste was solidified by drying at low temperature to give a
percutaneously absorbable preparation having a needle-like or
filamentous shape.
[0163] Mice, about 30 g body weight, were anesthetized by an
injection of pentobarbital and were fixed on the operating-table
after the hair of the abdomen was shaved. The percutaneously
absorbable preparation made in this example was inserted into the
shaved abdomen, and erythropoietin was administered percutaneously,
wherein the dose was 100 IU/kg. Blood samples were collected from
the jugular vein before and after administration for 5 hr. Serum
samples were obtained from the obtained blood samples and
erythropoietin concentrations were measured by an ELISA method.
Table 4 shows the result. That is, erythropoietin concentration
started to increase at 1 hr after administration and kept rising
until 5 hr. From these results, it was shown that erythropoietin
was administered percutaneously by the percutaneously absorbable
preparation of this example.
TABLE-US-00004 TABLE 4 Elapsed time after administration (hr)
before admini- stration 1 2 3 4 5 Erythro- ND 8 .+-. 4 11 .+-. 5 18
.+-. 6 26 .+-. 5 36 .+-. 5 poietin concen- tration (IU/mL)
EXAMPLE 7
[0164] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in a base consisting of
human serum albumin and hydroxypropyl cellulose.
[0165] About 0.2 mL of distilled water was added to 150 mg of human
serum albumin and 25 mg of hydroxypropyl cellulose (L-HPC, Nippon
Soda) to be dissolved. The solution was mixed well to give a base
paste consisting of human serum albumin and hydroxypropyl
cellulose. Ten .mu.L of sodium insulin solution (100 mg/mL, private
processed product) was added to 100 mg of this base paste and well
mixed so that insulin was held in the base paste. To the base paste
holding insulin, a top of a polypropylene stick of which diameter
was about 2 mm was attached. Thereafter, the top was gradually
pulled apart so that the base paste attaching to the top has a
needle-like or filamentous shape. In addition, a wire of 20 .mu.m
in the diameter was attached to a part of the surface of the
needle-like or filamentous base, where the part is near the
boundary between the base and the top, and a constricted line for
cut was made by rotating the wire. The needle-like or filamentous
base paste with the constricted line was solidified by drying at
low temperature to give a percutaneously absorbable preparation
having a needle-like or filamentous shape.
EXAMPLE 8
[0166] This example illustrates a percutaneously absorbable
preparation on which moisture-proof layer was formed with
polyethylene glycol, wherein the preparation has a needle-like and
filamentous shape and contains insulin (active substance) held in a
base consisting of dextrin.
[0167] About 1.0 mL of distilled water was added to 2 g of dextrin
(Wako Pure Chemical Industries) to be dissolved. The solution was
mixed well with motor and pestle to give a base paste consisting of
dextrin. Ten .mu.L of sodium insulin solution (100 mg/mL, private
processed product) was added to 100 mg of this base paste and well
mixed so that insulin was held in the base paste. To the base paste
holding insulin, a top of a glass stick of which diameter was about
3 mm was attached. Thereafter, the top was gradually pulled apart
so that the base paste attaching to the top has a needle-like or
filamentous shape. In addition, a wire of 20 .mu.m in the diameter
was attached to a part of the surface of the needle-like or
filamentous base, where the part is near the boundary between the
base and the top, and a constricted line for cut was made by
rotating the wire. The needle-like or filamentous base with the
constricted line was solidified by drying at low temperature to
give a solid preparation having a needle-like or filamentous shape.
On the other hand, methylene chloride solution containing 5% of
polyethylene glycol 20000 (PEG20000, Nacalai Tesque) was made. The
obtained solid preparation having a needle-like or filamentous
shape was soaked in this solution at the position of the
constricted line and coating on the surface of the solid
preparation was performed with PEG 20,000 after drying in air.
Thus, a percutaneously absorbable preparation having a needle-like
and filamentous shape and having moisture-proof layer on its
surface was prepared.
EXAMPLE 9
[0168] This example illustrates a percutaneously absorbable
preparation on which moisture-proof layer was formed with
polyethylene glycol, wherein the preparation has a needle-like and
filamentous shape and contains insulin (active substance) held in a
base consisting of gelatin and dextrin.
[0169] About 3 .mu.L of distilled water was added to 3 g of gelatin
(Wako Pure Chemical Industries) and 0.8 g of dextrin (Wako Pure
Chemical Industries) to be dissolved. The solution was mixed well
at about 50.degree. C. with motor and pestle to give a base paste
consisting of gelatin and dextrin. Ten .mu.L of sodium insulin
solution (100 mg/mL, private processed product) was added to 100 mg
of this base paste and well mixed so that insulin was held in the
base paste. Thereafter, a needle-like and filamentous solid
preparation with a constricted line was obtained in the same way as
Example 8. In addition, the surface of the solid preparation was
coated with PEG 20000 in the same way as Example 8. Thus, a
percutaneously absorbable preparation having a needle-like and
filamentous shape and having moisture-proof layer on its surface
was prepared.
EXAMPLE 10
[0170] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape, containing
insulin (active substance) held in a base consisting of gelatin and
dextrin, and further containing soybean trypsin inhibitor
(stabilizer).
[0171] About 3 mL of distilled water was added to 3 g of gelatin
(Wako Pure Chemical Industries), 0.8 g of dextrin (Wako Pure
Chemical Industries) and 1 mg of soybean trypsin inhibitor (Sigma)
to be dissolved. The solution was mixed well at about 40.degree. C.
with motor and pestle to give a base paste consisting of gelatin
and dextrin and containing soybean trypsin inhibitor. Ten .mu.L of
sodium insulin solution (100 mg/mL, private processed product) was
added to 100 mg of this base paste and well mixed so that insulin
was held in the base paste. On the other hand, a mold having a
needle-like or filamentous shape was made by inserting a sewing
needle into a plate made of perfluoroalkoxy (PFA) resin with a
hammer. The base paste holding insulin was introduced into this
mold at 40.degree. C. The introduced base paste was solidified by
cooling after left at room temperature to give a solid preparation.
The solid preparation was removed from the mold to give a
percutaneously absorbable preparation having a needle-like or
filamentous shape.
EXAMPLE 11
[0172] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape, containing
low molecular weight heparin (active substance) held in a base
consisting of sodium chondroitin sulfate C, and further containing
PEG 20,000 (thread-reducing agent) and caprylic acid (absorption
enhancer).
[0173] Fifty .mu.L of 5% PEG 20,000 (Nacalai Tesque) solution was
added to 100 mg of sodium chondroitin sulfate C (Nacalai Tesque) to
be dissolved. The solution was mixed well with motor and pestle to
give a base paste consisting of chondroitin sulfate C and
containing PEG 20,000. To this base, 5 mg of low molecular weight
heparin (Pamaparin) and 5 mg of capric acid (Wako Pure Chemical
Industries) were added and well mixed so that low molecular weight
heparin and capric acid were held in the base paste. To this base
paste holding low molecular weight heparin and capric acid, a top
of a glass stick of which diameter was about 2 mm was attached.
Thereafter, the top was gradually pulled apart so that the base
paste attaching to the top has a needle-like or filamentous shape.
In addition, a secant was made on the surface of the needle-like or
filamentous base paste with a wire of which diameter was 20 .mu.m.
The needle-like or filamentous base paste with the secant was
solidified by drying at low temperature to give a percutaneously
absorbable preparation having a needle-like or filamentous shape.
Evaluation in animal experiment using mice was performed as the
same method as Example 12 after-described.
EXAMPLE 12
[0174] This example illustrates a percutaneously absorbable
preparation which was the same as that of Example 11 but does not
have a secant.
[0175] A base paste consisting of sodium chondroitin sulfate C and
containing PEG 20,000 was prepared in the same way as Example 11.
Further, low molecular weight heparin and capric acid were held in
the base paste in the same way as Example 11. To this base paste
holding low molecular weight heparin and capric acid, a top of a
glass stick of which diameter was about 3 mm was attached.
Thereafter, the top was gradually pulled apart so that the base
paste attaching to the top has a needle-like or filamentous shape.
The needle-like or filamentous base paste was solidified by drying
at low temperature to give a percutaneously absorbable preparation
having a needle-like or filamentous shape.
[0176] As a comparative example against Examples 11 and 12, a
percutaneously absorbable preparation which was the same as that of
Example 11 but does not contain caprylic acid was made.
[0177] Mice, about 30 g body weight, were anesthetized by an
injection of pentobarbital and were fixed on the operating-table
after the hair of the abdomen was shaved. Percutaneously absorbable
preparations made in Example 11, Example 12 and comparative
examples were inserted into the shaved abdominal skin respectively,
and low molecular weight heparin was administered percutaneously.
The dose was 100 IU/kg. Blood samples were collected from the
jugular vein for 4 hr after administration. Blood samples were
obtained. Serum sample was prepared from the obtained each blood
sample, and heparin activity (anti-Xa activity) of each sample was
measured with Hemos IL.TM. Assay Kit (Instrumentation Laboratory,
United States). Table 5 shows the result. With the percutaneously
absorbable preparations of Examples 11 and 12, anti-Xa activity
started to increase at 1 or 2 hr after administration and showed
the maximum value at 3 hr after administration. On the other hand,
in the percutaneously absorbable preparations of comparative
example, anti-Xa activity was not detected even at 4 hr after
administration. Therefore, when the low molecular weight heparin is
the active substance, it was shown that an absorption enhancer such
as caprylic acid was necessary.
TABLE-US-00005 TABLE 5 Elapsed time after administration (hr)
before admini- stration 1 2 3 4 Anti-Xa Example 11 ND ND 0.13 .+-.
0.05 0.21 .+-. 0.08 0.19 .+-. 0.05 activity Example 12 ND 0.12 .+-.
0.04 0.19 .+-. 0.07 0.20 .+-. 0.08 0.17 .+-. 0.07 (IU/mL)
Comparative ND ND ND ND ND example
EXAMPLE 13
[0178] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing interferon (active substance) held in a base consisting
of glycogen.
[0179] About 1 mL of distilled water was added to 1 g of glycogen
(Nacalai Tesque) to be dissolved. The solution was mixed well under
warm to give a base paste consisting of glycogen. To this base, 10
.mu.L of interferon alpha injection solution "Sumiferon"
(Trademark, 6,000,000 units/mL, Sumitomo Pharmaceuticals)
corresponding to 60,000 IU was added and well mixed so that
interferon was held in the base paste. To this base paste holding
interferon, a top of a glass stick of which diameter was about 3 mm
was attached. Thereafter, the top was gradually pulled apart so
that the base paste attaching to the top has a needle-like or
filamentous shape. The needle-like or filamentous base paste was
solidified by drying at low temperature to give a percutaneously
absorbable preparation having a needle-like or filamentous
shape.
EXAMPLE 14
[0180] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape, containing
insulin (active substance) held in a base consisting of
carboxyvinyl polymer, and further containing PEG 20,000
(thread-reducing agent).
[0181] Two mL of 1% PEG 20,000 (Nacalai Tesque) solution was added
to 3 g of carboxyvinyl polymer (Nacalai Tesque) to be dissolved.
The solution was mixed well to give a base paste consisting of
carboxyvinyl polymer and containing PEG 20,000. To 100 mg of this
base paste, 10 .mu.L of sodium insulin solution (100 mg/mL, private
processed product) was added and well mixed so that insulin was
held in the base paste. To this base paste, a top of a
polypropylene stick of which diameter was about 3 mm was attached.
Thereafter, the top was gradually pulled apart so that the base
paste attaching to the top has a needle-like or filamentous shape.
After a constricted line for cut was made in the same way as
Example 8, the needle-like or filamentous base paste with the
constricted line was solidified by drying at low temperature to
give a percutaneously absorbable preparation having a needle-like
or filamentous shape.
EXAMPLE 15
[0182] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing vitamin C (active substance) held in a base consisting
of dextran and hyaluronic acid.
[0183] About 50 .mu.L of distilled water was added to 80 mg of
dextran (molecular weight 170,000-200,000, Nacalai Tesque), 2 mg of
hyaluronic acid (mean molecular weight 90,000, commodity code:
FCH-SU, Kibun Food Chemifa Co.) and 5 mg of vitamin C (L-ascorbic
acid, Wako Pure Chemical Industries) to be dissolved. The solution
was mixed well to give a base paste consisting of dextran and
hyaluronic acid and holding vitamin C. To this base paste holding
vitamin C, a top of a glass stick of which diameter was about 3 mm
was attached. Thereafter, the top was gradually pulled apart so
that the base paste attaching to the top has a needle-like or
filamentous shape. The needle-like or filamentous base paste was
solidified by drying at low temperature to give a percutaneously
absorbable preparation having a needle-like or filamentous
shape.
EXAMPLE 16
[0184] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing vitamin C (active substance) held in a base consisting
of pullulan and hyaluronic acid.
[0185] About 50 .mu.L of distilled water was added to 50 mg of
pullulan (commodity code: PI-20, Hayashibara Shoji, Inc.), 1 mg of
hyaluronic acid (mean molecular weight 90,000, commodity code:
FCH-SU, Kibun Food Chemifa Co.) and 2 mg of vitamin C (L-ascorbic
acid, Wako Pure Chemical Industries) to be dissolved. The solution
was mixed well to give a base paste consisting of pullulan and
hyaluronic acid and holding vitamin C. To this base paste holding
vitamin C, a top of a glass stick of which diameter was about 3 mm
was attached. Thereafter, the top was gradually pulled apart so
that the base paste attaching to the top has a needle-like or
filamentous shape. The needle-like or filamentous base paste was
solidified by drying at low temperature to give a percutaneously
absorbable preparation having a needle-like or filamentous
shape.
EXAMPLE 17
[0186] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing low molecular weight heparin (active substance) held in
a base consisting of human serum albumin.
[0187] About 0.2 mL of distilled water was added to 150 mg of human
serum albumin to be dissolved. The solution was mixed well to give
a base paste consisting of human serum albumin. To this base paste,
5 mg of low molecular weight heparin (Parnaparin) was added and
well mixed so that low molecular weight heparin was held in the
base paste. To this base paste, a top of a glass stick of which
diameter was about 2 mm was attached. Thereafter, the top was
gradually pulled apart so that the base paste attaching to the top
has a needle-like or filamentous shape. The needle-like or
filamentous base paste was solidified by drying in air to give a
percutaneously absorbable preparation having a needle-like or
filamentous shape.
[0188] Mice, about 30 g body weight, were anesthetized by an
injection of pentobarbital and were fixed on the operating-table
after the hair of the abdomen was shaved. A percutaneously
absorbable preparation made in this example was inserted into the
shaved abdominal skin respectively, and low molecular weight
heparin was administered percutaneously. The dose was 100 IU/kg.
Systemic blood samples were collected from the jugular vein for 6
hr after administration. Serum sample was prepared from the
obtained each blood sample, and heparin activity (anti-Xa activity)
of each sample was measured with Hemos IL Assay Kit
(Instrumentation Laboratory, United States). Table 6 shows the
result. That is, serum anti-Xa activities were lower than its level
of quantitation, 0.1 IU/mL, before administration and at 1 hr after
administration. Thereafter, anti-Xa activity increased gradually
till 4 hr. Therefore, it was shown that low molecular weight
heparin was administered percutaneously with a percutaneously
absorbable preparation of this example.
TABLE-US-00006 TABLE 6 Elapsed time after administration (hr)
before adminis- tration 1 2 3 4 5 6 Anti-Xa ND ND 0.13 0.21 0.18
0.14 0.11 activity (IU/mL)
EXAMPLE 18
[0189] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing low molecular weight heparin (active substance) held in
a base consisting of human serum albumin, where the low molecular
weight heparin was released with a sustained-released manner.
[0190] According to the same method as Example 17, a solid
preparation having a needle-like or filamentous shape was obtained.
On the other hand, 2 .mu.L of 25% glutaraldehyde solution (Nacalai
Tesque) was added to 10 mL of ethanol and was mixed well. To this
mixture, the obtained solid preparation was soaked for 5 min and
cross-linking treatment was performed on its surface. The treated
solid preparation was soaked in ethanol and water for 30 sec,
respectively and the surface was washed. The washed solid
preparation was dried in air to give a percutaneously absorbable
preparation having a needle-like or filamentous shape.
[0191] With the percutaneously absorbable preparation made in this
example, dissolution experiment was performed for 5 hr at
37.degree. C. Ten mL of dissolution test medium was prepared by
diluting rat skin homogenate to ten times with isotonic phosphate
buffer (pH7.4). The anti-Xa activity of the dissolution test medium
was measured by using the above-mentioned Hemos IL Heparin Assay
Kit. As a reference, the percutaneously absorbable preparation made
in Example 17 was used and the same study was performed. Table 7
shows the result. That is, the anti-Xa activity was not detected
until 10 min after the start of the dissolution experiment. At 30
min after the start of the experiment, anti-Xa activity was
initially detected. Moreover, anti-Xa activity showed high values
at 3 hr after the start of the experiment. On the other hand, in
the case of the percutaneously absorbable preparation made in
Example 17, anti-Xa activity started to be detected at 2 min after
the start of the experiment. Thus, it was shown that low molecular
weight heparin was released from the percutaneously absorbable
preparation made in this example with a sustained-release
manner.
TABLE-US-00007 TABLE 7 Elapsed time after the start of dissolution
experiment (min) 0 1 2 3 4 5 10 30 60 120 180 Anti-Xa activity
Example ND ND 0.10 0.16 0.18 0.19 0.19 0.19 0.19 0.19 0.19 (IU/mL)
17 Example ND ND ND ND ND ND ND 0.09 0.12 0.18 0.19 18
EXAMPLE 19
[0192] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in a base consisting of
human serum albumin, where the insulin was released with a
sustained-released manner.
[0193] About 0.2 mL of distilled water was added to 150 mg of human
serum albumin to be dissolved. The solution was mixed well to give
a base paste consisting of human serum albumin. To 100 mg of this
base, 10 .mu.L of sodium insulin solution (100 mg/mL, private
processed product) was added well mixed so that insulin was held in
the base paste. To this base paste holding insulin, a top of a
polypropylene stick of which diameter was about 2 mm was attached.
Thereafter, the top was gradually pulled apart so that the base
paste attaching to the top has a needle-like or filamentous shape.
Thereafter, glutaraldehyde treatment was performed in the same way
as Example 18 to give a percutaneously absorbable preparation
having a needle-like or filamentous shape.
EXAMPLE 20
[0194] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in porous anhydrous
silicate or porous calcium silicate (porous material), where the
insulin was released with a sustained-released manner.
[0195] Four kinds of porous anhydrous silicates (Trade names:
Sylysia350, Sylysia440, Sylysia550 and Sylysia730 (Fuji Silysia
Co., Ltd. Aichi, Japan)), and one kind of porous calcium silicate
(Trade name: Florite RE, Eisai) were examined as porous materials.
In the following, example using Sylysia 350 is named Example 20-1,
example using Sylysia 440 is named Example 20-2, example using
Sylysia 550 is named Example 20-3, example using Sylysia 730 is
named Example 20-4 and example using Florite is named Example 20-5.
On the other hand, bovine pancreatic insulin (Wako Pure Chemical
Industries) was dissolved with distilled water to give 9.6 mg/mL
insulin solution. To 15.9 mg of porous material, 0.1 mL of the
insulin solution was added. The solution was mixed well and dried
to give insulin-adsorbed powder. On the other hand, about 0.15 mL
of distilled water was added to 317.5 mg of sodium chondroitin
sulfate C (Nacalai Tesque) to be dissolved. The solution was mixed
well to give a base paste consisting of sodium chondroitin sulfate
C. To this base paste, 16.86 mg of insulin-adsorbed powder was
added and mixed well. To this base paste containing porous material
in which insulin was held, a top of a glass stick of which diameter
was about 3 mm was attached. Thereafter, the top was gradually
pulled apart so that the base paste attaching to the top has a
needle-like or filamentous shape. The needle-like or filamentous
base paste was solidified by drying at low temperature to give a
percutaneously absorbable preparation having a needle-like or
filamentous shape, resulting in giving five kinds of percutaneously
absorbable preparations. Evaluation in animal experiment using mice
was performed at the same time with Example 21 after-described.
EXAMPLE 21
[0196] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape, containing
middle-acting insulin (active substance) held in a base, and
further containing L-glutamic acid-L-lysine (thread-reducing
reagent), where the insulin was released with a sustained-released
manner.
[0197] About 0.45 mL of distilled water was added to 312.8 mg of
sodium chondroitin sulfate C (Nacalai Tesque) and 153.8 mg of
L-glutamic acid-L-lysine (Ajinomoto) to be dissolved. The solution
was mixed well to give a base paste consisting of sodium
chondroitin sulfate C. To this base paste, 0.167 IU of
middle-acting insulin (Penfil N.TM., NovoNordisc) was added and
well mixed so that middle-acting insulin was held in the base
paste. To this base paste holding middle-acting insulin, a top of a
glass stick of which diameter was about 3 mm was attached.
Thereafter, the top was gradually pulled apart so that the base
paste attaching to the top has a needle-like or filamentous shape.
The needle-like or filamentous base paste was solidified by drying
at low temperature to give a percutaneously absorbable preparation
having a needle-like or filamentous shape.
[0198] The percutaneously absorbable preparations made in Examples
20 and 21 were evaluated by means of hypoglycemic effect in mice.
More specifically, mice, about 30 g body weight, were anesthetized
by an injection of pentobarbital and were fixed on the
operating-table after the hair of the abdomen was shaved.
Percutaneously absorbable preparations made in Example 20 or 21
were inserted into the mice abdominal skin and insulin was
administered percutaneously. The dose was 2.5 IU/kg. Systemic blood
was removed before and after administration for 24 hr. Serum
samples were prepared from the obtained blood samples and glucose
concentration in each serum sample was measured using glucose assay
kit (Glucose C II-Test kit, Wako Pure Chemical Industries). Each
glucose level was shown as a relative value to the pre-dose level,
100%. All data were calculated as the mean +/-standard deviation
(SD), wherein each group consists of three to four mice. The result
is shown in FIGS. 16A and 16B. These figures show the time course
of blood glucose levels when percutaneously absorbable preparations
of Example 20 or 21 were inserted into the skin. FIG. 16A shows the
time course of blood glucose levels when percutaneously absorbable
preparations of Example 20-1, 20-2 or 20-3 were inserted into the
skin. FIG. 16B shows the time course of blood glucose levels when
percutaneously absorbable preparations of Example 20-4, 20-5 or 21
were inserted into the skin. The ordinate of FIGS. 16A and 16B is
blood glucose level and abscissa is the time. Control is the case
where percutaneously absorbable preparations consisting of only
base were used. As a result, in five kinds of the percutaneously
absorbable preparations of Example 20, serum glucose levels
decreased for 12 hr after administration. Furthermore, in the
percutaneously absorbable preparations of Example 21, serum glucose
levels decreased for 9 hr after administration. From these results,
it was shown that insulin was administered percutaneously with a
sustained-release manner by the percutaneously absorbable
preparations of Example 20 or 21.
EXAMPLE 22
[0199] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in a base consisting of
hyaluronic acid and dextran.
[0200] Thirty holes of about 1 mm in the diameter were made on an
acrylic plate of about 2.0 mm in thickness. Sawing needles were
penetrated to these holes and were fixed where the needle top comes
out of the surface of an acrylic plate about 200 .mu.m. In
addition, adhesive glue was injected from the inserted side of the
needles and the needles were fixed to an acrylic plate. On the
other hand, silicon resin was put in a petri dish. An acrylic plate
with the above-mentioned needles was put on the silicon resin in
the petri dish, and was left overnight. An acrylic plate with
needles was removed after the silicon resin was confirmed to be
solid, and the mold made of the silicon resin was made.
[0201] To 2.4 mg of hyaluronic acid (mean molecular weight: 90,000,
commodity code: FCH-SU by Kibun Food Chemifa Co., Ltd.) and 2.4 mg
of dextran (molecular weight: 50,000-70,000, Nacarai Tesque) to be
dissolved, 2.5 .mu.L of distilled water was added. The solution was
mixed well to give a base paste consisting of hyaluronic acid and
dextran. To this base paste, 0.2 mg of sodium insulin (private
processed product) solution was added and well mixed so that
insulin was held in the base paste. The base paste holding insulin
was filled into the mold made of silicon. The filled base paste was
solidified by drying at low temperature. The solidified base was
removed from the mold to give a percutaneously absorbable
preparation having a needle-like or filamentous shape.
EXAMPLE 23
[0202] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing vitamin C (active substance) held in a base consisting
of chitosan.
[0203] One hundred .mu.L of acetic acid and about 1 mL of distilled
water were added to 0.3 g of chitosan (Daikitosan VL, Dainichiseika
Color & Chemicals Mfg. Co., Ltd.) to be dissolved. The solution
was mixed well under stirring on a hot plate stirrer. Further, 1N
NaOH solution was added so that pH of the solution was adjusted to
about 6.5. This solution was stirred under warm air blow and water
was evaporated to give a base paste consisting of chitosan. To this
base paste, 5 mg of vitamin C (L-ascorbic acid, Wako Pure Chemical
Industries) was added and well mixed so that vitamin C was held in
the base paste. The base paste holding vitamin C was filled into
the mold in the same way as Example 22. The filled base paste was
solidified by drying at low temperature to give a percutaneously
absorbable preparation having a needle-like or filamentous
shape.
EXAMPLE 24
[0204] This example illustrates a percutaneously absorbable
preparation having a needle-like and filamentous shape and
containing insulin (active substance) held in a base consisting of
sodium chondroitin sulfate C, where the insulin was released with a
sustained-released manner.
[0205] To 4.8 mg of sodium chondroitin sulfate C (Nacalai Tesque)
to be dissolved, 2.5 .mu.L of distilled water was added. The
solution was mixed well to give a base paste consisting of sodium
chondroitin sulfate C. To this base paste, 0.2 mg of sodium insulin
(private processed product) was added and well mixed so that
insulin was held in the base paste. To this base holding sodium
chondroitin sulfate C, a top of a polypropylene tip was attached.
Thereafter, the top was gradually pulled apart so that the base
paste attaching to the top has a needle-like or filamentous shape.
The needle-like or filamentous base paste was soaked in a saturated
calcium chloride solution for 1 hr at 4.degree. C. and was
hardened. Through this process, water-insoluble layer was made on
its surface. The layer was dried in air to give a percutaneously
absorbable preparation having a needle-like or filamentous
shape.
* * * * *