U.S. patent application number 16/088041 was filed with the patent office on 2019-07-18 for fast-eluting three-dimensionally molded object, filament for fast-eluting three-dimensionally molded object, and material for fa.
This patent application is currently assigned to ASTELLAS PHARMA INC.. The applicant listed for this patent is ASTELLAS PHARMA INC.. Invention is credited to Shota HATTORI, SORATO IKEDA, Masanori KOBAYASHI.
Application Number | 20190217531 16/088041 |
Document ID | / |
Family ID | 60001250 |
Filed Date | 2019-07-18 |
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United States Patent
Application |
20190217531 |
Kind Code |
A1 |
IKEDA; SORATO ; et
al. |
July 18, 2019 |
FAST-ELUTING THREE-DIMENSIONALLY MOLDED OBJECT, FILAMENT FOR
FAST-ELUTING THREE-DIMENSIONALLY MOLDED OBJECT, AND MATERIAL FOR
FAST-ELUTING THREE-DIMENSIONALLY MOLDED OBJECT
Abstract
Provided is a fast-eluting three-dimensionally molded object,
which is formed by fused deposition modeling type three-dimensional
molding and quickly elutes an active component. The fast-eluting
three-dimensionally molded object is formed by the fused deposition
modeling type three-dimensional molding and includes an active
component, a water-soluble thermoplastic polymer, a water-soluble
sugar and/or a water-soluble sugar alcohol, and a plasticizer
component. The fast-eluting three-dimensionally molded object has
an elution rate of the active component of 80% or higher within 85
minutes by a dissolution test method in the Japanese Pharmacopoeia,
Sixteenth Edition.
Inventors: |
IKEDA; SORATO; (Tokyo,
JP) ; HATTORI; Shota; (Tokyo, JP) ; KOBAYASHI;
Masanori; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ASTELLAS PHARMA INC. |
Tokyo |
|
JP |
|
|
Assignee: |
ASTELLAS PHARMA INC.
Tokyo
JP
|
Family ID: |
60001250 |
Appl. No.: |
16/088041 |
Filed: |
April 5, 2017 |
PCT Filed: |
April 5, 2017 |
PCT NO: |
PCT/JP2017/014205 |
371 Date: |
September 24, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2095 20130101;
C08L 33/14 20130101; A61K 9/2018 20130101; B33Y 10/00 20141201;
A61K 47/10 20130101; C08K 5/1545 20130101; C08L 39/06 20130101;
B29C 64/118 20170801; B29K 2029/04 20130101; A61K 47/32 20130101;
A61K 47/34 20130101; C08L 29/04 20130101; A61K 47/26 20130101; B33Y
80/00 20141201; B29K 2033/04 20130101; B33Y 70/00 20141201; A61K
9/2027 20130101; A61K 9/20 20130101; B29K 2039/06 20130101; A61K
31/506 20130101 |
International
Class: |
B29C 64/118 20060101
B29C064/118; C08L 29/04 20060101 C08L029/04; C08L 39/06 20060101
C08L039/06; C08L 33/14 20060101 C08L033/14; C08K 5/1545 20060101
C08K005/1545 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 6, 2016 |
JP |
2016-076810 |
Claims
1. A fast-eluting three-dimensionally molded object formed by fused
deposition modeling type three-dimensional molding, comprising: an
active component; a water-soluble thermoplastic polymer; a
water-soluble sugar and/or a water-soluble sugar alcohol; and a
plasticizer component.
2. The fast-eluting three-dimensionally molded object according to
claim 1, wherein an elution rate of the active component by a
paddle method of a dissolution test method in the Japanese
Pharmacopoeia, Sixteenth Edition, is 80% or higher within 85
minutes.
3. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the water-soluble sugar and/or the water-soluble
sugar alcohol has a glass transition temperature of a room
temperature or higher.
4. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the water-soluble sugar and/or the water-soluble
sugar alcohol is one or more kinds selected from a group consisting
of sucrose, maltitol, xylitol, mannitol, erythritol, sorbitol,
isomalt, and lactitol.
5. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the water-soluble sugar and/or the water-soluble
sugar alcohol is one or more kinds selected from a group consisting
of maltitol, xylitol, mannitol, erythritol, sorbitol, isomalt, and
lactitol.
6. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the water-soluble thermoplastic polymer is one or
more kinds selected from a group consisting of a polyvinyl alcohol,
a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft
copolymer, polyethylene oxide, polyvinylpyrrolidone, copolyvidone,
a polyethylene glycol-polyvinyl alcohol-graft copolymer, a
polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer,
aminoalkyl methacrylate copolymer RS, and aminoalkyl methacrylate
copolymer E.
7. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the water-soluble thermoplastic polymer is one or
more kinds selected from a group consisting of a polyvinyl alcohol,
polyvinylpyrrolidone, and aminoalkyl methacrylate copolymer E.
8. The fast-eluting three-dimensionally molded object according to
claim 1, wherein: the water-soluble thermoplastic polymer is one or
more kinds selected from a group consisting of a polyvinyl alcohol,
polyvinylpyrrolidone, and aminoalkyl methacrylate copolymer E; and
the water-soluble sugar and/or the water-soluble sugar alcohol is
maltitol.
9. The fast-eluting three-dimensionally molded object according to
claim 1, wherein a content of the water-soluble sugar and/or the
water-soluble sugar alcohol is 10 to 65 wt. % with respect to a
total weight of the three-dimensionally molded object.
10. The fast-eluting three-dimensionally molded object according to
claim 1, wherein a content of the water-soluble thermoplastic
polymer is 20 to 90 wt. % with respect to the total weight of the
three-dimensionally molded object.
11. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the elution rate of the active component is 80% or
higher within 30 minutes.
12. The fast-eluting three-dimensionally molded object according to
claim 1, wherein the fast-eluting three-dimensionally molded object
is a ring-shaped solid object.
13. A filament for fast-eluting three-dimensionally molded object
used for forming a three-dimensionally molded object by fused
deposition modeling type three-dimensional molding, comprising: an
active component; a water-soluble thermoplastic polymer; a
water-soluble sugar and/or a water-soluble sugar alcohol; and a
plasticizer component.
14. A material for fast-eluting three-dimensionally molded object
used for forming a three-dimensionally molded object by fused
deposition modeling type three-dimensional molding, comprising: an
active component; a water-soluble thermoplastic polymer; a
water-soluble sugar and/or a water-soluble sugar alcohol; and a
plasticizer component.
Description
TECHNICAL FIELD
[0001] The present invention relates to a fast-eluting
three-dimensionally molded object, a filament for fast-eluting
three-dimensionally molded object, and a material for fast-eluting
three-dimensionally molded object. In particular, the present
invention relates to a fast-eluting three-dimensionally molded
object formed by fused deposition modeling type three-dimensional
molding, a filament for fast-eluting three-dimensionally molded
object for the fused deposition modeling, and a material for
fast-eluting three-dimensionally molded object for the fused
deposition modeling.
BACKGROUND ART
[0002] Conventionally, there has been known a 3D printing technique
capable of molding a three-dimensionally molded object by
three-dimensionally laminating and arranging a material for
three-dimensionally molded object using 3D-CAD (computer-aided
design) data created by a computer as a design plan.
[0003] The 3D printing technique can be classified into a plurality
of groups mainly in accordance with a difference in a type of
lamination. Examples of the 3D printing technique includes fused
deposition modeling (FDM) in which a thermoplastic resin serving as
a material for three-dimensionally molded object is thermally
melted, extruded from a nozzle, and molded while being laminated on
a molding stage and powder bed printing in which a powdery resin
serving as a material for three-dimensionally molded object is laid
over a molding stage and then a binder is sprayed on the powdery
resin. Other techniques include stereolithography, powder selective
laser sintering, and the like.
[0004] Under such circumstances, as the invention of a material for
three-dimensionally molded object used in the fused deposition
modeling, Patent literature 1, for example, discloses a material
that develops little warpage and is easily subjected to surface
polishing. It is disclosed that using such a material is
advantageous for producing an industrial part having a new shape,
confirming a design in a pre-production stage, and the like.
[0005] Moreover, recently, levetiracetam produced in a solid form
using a 3D printer has been approved as a drug product under a name
of SPRITAM (registered trademark) by U.S. Food and Drug
Administration (FDA). As shown in such an example, the 3D printer
is gaining attention as a new production method of a pharmaceutical
preparation.
[0006] For example, Non patent literature 1 discloses an
extended-release patient-tailored prednisolone tablet produced by
the fused deposition modeling type three-dimensional molding.
[0007] It is disclosed that the prednisolone tablet includes a
water-soluble thermoplastic polymer (a polyvinyl alcohol) as a base
and has an elution rate of prednisolone serving as a
pharmaceutically active component of 80% or higher in about 8 to 18
hours.
[0008] Further, for example, Non patent literature 2 discloses a
tablet that is produced by the fused deposition modeling type
three-dimensional molding and allows an adjustment of a drug
dose.
[0009] It is disclosed that the tablet includes a polyvinyl alcohol
as abase and has an elution rate of fluorescein serving as a model
drug of 80% or higher in about 4.5 to 9 hours.
[0010] Further, for example, Non patent literature 3 discloses a
tablet that is produced by the fused deposition modeling type
three-dimensional molding and includes 4-aminosalicylic acid or
5-aminosalicylic acid in a modified-release formulation.
[0011] It is disclosed that the tablet includes a polyvinyl alcohol
as a base and has an elution rate of 5-aminosalicylic acid of 80%
or higher in about 1.5 to 2.5 hours.
CITATION LIST
Patent Literature
[0012] PATENT LITERATURE 1: JP 5751388 B1
Non Patent Literature
[0012] [0013] NON PATENT LITERATURE 1: European Journal of
Pharmaceutical Sciences 68 (2015) 11-17 [0014] NON PATENT
LITERATURE 2: International Journal of Pharmaceutics 476 (2014)
88-92 [0015] NON PATENT LITERATURE 3: European Journal of
Pharmaceutics and Biopharmaceutics 89 (2015) 157-162
SUMMARY OF INVENTION
Technical Problem
[0016] It is generally considered that the fused deposition
modeling and the powder bed printing are adopted to produce a solid
object (a three-dimensionally molded object) using the 3D printer.
However, when the production is performed by the powder bed
printing, the strength of the three-dimensionally molded object
becomes relatively weak, thereby causing a risk of breakage of the
solid object, such as cracking and chipping, during a distribution
process. Further, when the fused deposition modeling is adopted,
the solid object hardly collapses, thereby causing a problem of
reducing an elution rate of an active component.
[0017] Thus, it has been demanded to develop a solid object that
elutes the active component relatively quickly while maintaining
excellent injection moldability and printability by adopting the
fused deposition modeling.
[0018] Specifically, it has been demanded to develop a fast-eluting
solid object that is prepared so as to further increase the elution
rate of the active component as compared to the solid object such
as the one in Non patent literatures 1, 2, and 3.
[0019] Further, a technique capable of suitably performing the
three-dimensional molding of the solid object has been
demanded.
[0020] The present invention is made in light of the
above-mentioned problems, and an object of the present invention is
to provide a fast-eluting three-dimensionally molded object, which
is formed by fused deposition modeling type three-dimensional
molding and quickly elutes an active component.
[0021] Further, another object of the present invention is to
provide a filament for fast-eluting three-dimensionally molded
object and a material for fast-eluting three-dimensionally molded
object used for forming the fast-eluting three-dimensionally molded
object by the fused deposition modeling type three-dimensional
molding.
[0022] Further, another object of the present invention is to
provide the fast-eluting three-dimensionally molded object, the
filament for fast-eluting three-dimensionally molded object, and
the material for fast-eluting three-dimensionally molded object,
which exhibit excellent injection moldability and printability in
performing the three-dimensional molding by the fused deposition
modeling.
Solution to Problem
[0023] The present inventors have conducted intensive studies and
found that a three-dimensionally molded object that elutes an
active component relatively quickly can be produced when a material
for three-dimensionally molded object used for the fused deposition
modeling type three-dimensional molding includes the active
component, a water-soluble thermoplastic polymer, a water-soluble
sugar and/or a water-soluble sugar alcohol, and a plasticizer
component, thereby completing the present invention.
[0024] Further, the present inventors have found that the material
for three-dimensionally molded object exhibits excellent injection
moldability in producing the filament for three-dimensionally
molded object and excellent printability in performing the
three-dimensional molding by the fused deposition modeling, thereby
completing the present invention.
[0025] Thus, according to the present invention, the
above-mentioned problems can be solved by a three-dimensionally
molded object, which is formed by fused deposition modeling type
three-dimensional molding and includes an active component, a
water-soluble thermoplastic polymer, a water-soluble sugar and/or a
water-soluble sugar alcohol, and a plasticizer component.
[0026] Having the above configuration can achieve a fast-eluting
three-dimensionally molded object.
[0027] Further, the three-dimensionally molded object that exhibits
excellent injection moldability and printability can be achieve by
performing the three-dimensional molding by the fused deposition
modeling.
[0028] In the three-dimensionally molded object, an elution rate of
the active component by a paddle method of a dissolution test
method in the Japanese Pharmacopoeia, Sixteenth Edition, is
preferably 80% or higher within 85 minutes.
[0029] Having the above configuration can achieve the fast-eluting
three-dimensionally molded object.
[0030] In the three-dimensionally molded object, the water-soluble
sugar and/or the water-soluble sugar alcohol has a glass transition
temperature of preferably a room temperature or higher.
[0031] The water-soluble sugar and/or the water-soluble sugar
alcohol is further preferably one or more kinds selected from the
group consisting of sucrose, maltitol, xylitol, mannitol,
erythritol, sorbitol, isomalt, and lactitol.
[0032] Further, the water-soluble sugar and/or the water-soluble
sugar alcohol is preferably one or more kinds selected from the
group consisting of maltitol, xylitol, mannitol, erythritol,
sorbitol, isomalt, and lactitol.
[0033] Further, the water-soluble thermoplastic polymer is
preferably one or more kinds selected from the group consisting of
a polyvinyl alcohol, a polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymer, polyethylene oxide,
polyvinylpyrrolidone, copolyvidone, a polyethylene glycol-polyvinyl
alcohol-graft copolymer, a polyvinyl alcohol-acrylic acid-methyl
methacrylate copolymer, aminoalkyl methacrylate copolymer RS, and
aminoalkyl methacrylate copolymer E.
[0034] Further, the water-soluble thermoplastic polymer is
preferably one or more kinds selected from the group consisting of
a polyvinyl alcohol, polyvinylpyrrolidone, and aminoalkyl
methacrylate copolymer E.
[0035] Further, it is preferable that the water-soluble
thermoplastic polymer is one or more kinds selected from the group
consisting of a polyvinyl alcohol, polyvinylpyrrolidone, and
aminoalkyl methacrylate copolymer E and the water-soluble sugar
and/or the water-soluble sugar alcohol is maltitol.
[0036] Further, the content of the water-soluble sugar and/or the
water-soluble sugar alcohol is preferably 10 to 65 wt. % with
respect to the total weight of the three-dimensionally molded
object.
[0037] Further, the content of the water-soluble thermoplastic
polymer is preferably 20 to 90 wt. % with respect to the total
weight of the three-dimensionally molded object.
[0038] As for the water-soluble thermoplastic polymer, the
water-soluble sugar and/or the water-soluble sugar alcohol, and the
plasticizer component, optimizing each of these materials and the
content thereof as described above can impart further excellent
injection moldability and printability and achieve the
three-dimensionally molded object adjustable to further increase
the elution rate of the active component.
[0039] In the three-dimensionally molded object, the elution rate
of the active component is preferably 80% or higher within 30
minutes.
[0040] Having the above configuration allows the production of the
three-dimensionally molded object exhibiting further faster
elutability as compared to the conventional three-dimensionally
molded object.
[0041] The three-dimensionally molded object is preferably a
ring-shaped solid object.
[0042] Having the above configuration can secure a larger surface
area of the solid object as compared to the conventional cylinder
or elliptical solid object, thus the elution of the active
component in the solid object can be adjusted to be faster.
[0043] Further, a filament for fast-eluting three-dimensionally
molded object and a material for fast-eluting three-dimensionally
molded object used for forming a three-dimensionally molded object
by fused deposition modeling type three-dimensional molding can be
achieved by including an active component, a water-soluble
thermoplastic polymer, a water-soluble sugar and/or a water-soluble
sugar alcohol, and a plasticizer component.
Advantageous Effects of Invention
[0044] According to the present invention, there can be provided
the fast-eluting three-dimensionally molded object, which is formed
by the fused deposition modeling type three-dimensional molding and
quickly elutes the active component.
[0045] Further, there can be provided the filament for fast-eluting
three-dimensionally molded object and the material for fast-eluting
three-dimensionally molded object used for forming the fast-eluting
three-dimensionally molded object by the fused deposition modeling
type three-dimensional molding.
[0046] Further, there can be provided the fast-eluting
three-dimensionally molded object, the filament for fast-eluting
three-dimensionally molded object, and the material for
fast-eluting three-dimensionally molded object, which exhibit
excellent injection moldability and printability in performing the
three-dimensional molding by the fused deposition modeling.
BRIEF DESCRIPTION OF DRAWINGS
[0047] FIG. 1 is result data of an elution test in Test example
[0048] FIG. 2A is a perspective view illustrating a solid object
(in a cylinder shape) in Example 2-1.
[0049] FIG. 2B is a perspective view illustrating a solid object
(in a ring shape 1) in Example 2-2.
[0050] FIG. 2C is a perspective view illustrating a solid object
(in a ring shape 2) in Example 2-3.
[0051] FIG. 3 is result data of the elution test using the solid
objects having different shapes in Test example 2.
[0052] FIG. 4 is result data of the elution test in Test
example
[0053] FIG. 5 is result data of an oral absorbability test in a dog
in Test example 4.
[0054] FIG. 6 is result data of the elution test in Test
example
[0055] FIG. 7 is result data of the elution test in Test
example
[0056] FIG. 8 is result data of the elution test in Test
example
[0057] FIG. 9 is result data of the elution test in Test
example
[0058] FIG. 10 is result data of the elution test in Test
example
[0059] FIG. 11 is result data of the elution test in Test
example
DESCRIPTION OF EMBODIMENTS
[0060] The following describes embodiments of the present invention
with reference to FIG. 1 to FIG. 11.
[0061] The present embodiments relate to the invention of a
fast-eluting three-dimensionally molded object, which is formed by
fused deposition modeling type three-dimensional molding and
characterized by including a pharmaceutically active component, a
polyvinyl alcohol, maltitol, and triethyl citrate.
[0062] Further, the present embodiments relate to the invention of
a filament for fast-eluting three-dimensionally molded object and a
material for fast-eluting three-dimensionally molded object used
for forming the fast-eluting three-dimensionally molded object
described above.
[0063] The term "material for three-dimensionally molded object"
refers to a fast-eluting material, which is suitably used for the
three-dimensional molding, in particular, for the fused deposition
modeling, and includes a component that can be used for oral
administration, oral ingestion, intraoral administration,
intrarectal administration, or vaginal administration.
[0064] The material for three-dimensionally molded object is, for
example, formed in a powder shape and obtained by appropriately
formulating each constituent component, however, the shape can be
changed without a particular limitation. For example, the powder
obtained by formulating each constituent component maybe granulated
to form a pellet.
[0065] The term "filament for three-dimensionally molded object"
refers to a product obtained by subjecting the material for
three-dimensionally molded object to melt-kneading with compression
and extrusion molding using an extruding machine (an extruder) or
the like. The filament for three-dimensionally molded object is
formed, for example, as a filamentous body having a diameter of
about 1.0 to 3.0 mm.
[0066] The term "three-dimensionally molded object" refers to a
product obtained by thermally melting the filament for
three-dimensionally molded object, extruding the melted filament
from a nozzle, and molding the melted filament layer by layer on a
molding stage using a fused deposition modeling type 3D printing
apparatus.
[0067] An administration route of the three-dimensionally molded
object is not particularly limited. Examples of the administration
route include oral administration or oral ingestion, intraoral
administration, intrarectal administration, vaginal administration,
and the like. Oral administration is preferable.
[0068] The three-dimensionally molded object is not limited to a
pharmaceutical and may be, for example, a solid food for oral
ingestion, such as a food for specified health uses, a food with
nutrient function claims, a food with function claims, and a
supplement.
[0069] The three-dimensionally molded object is preferably formed
in a ring shape. However, the shape may be changed without a
particular limitation. The three-dimensionally molded object may be
formed in a conventional cylinder or elliptical shape.
[0070] Next, each constituent component of the material for
three-dimensionally molded object will be described.
[0071] The material for three-dimensionally molded object includes
an active component, a water-soluble thermoplastic polymer, a
water-soluble sugar and/or a water-soluble sugar alcohol, and a
plasticizer component.
[0072] Note that the material for three-dimensionally molded object
may further include various additive components. For example, one
or more of a binder, a stabilizer, a disintegrating agent, a
disintegrating assistant, an acidulant, a foaming agent, an
artificial sweetener, a flavoring agent, a lubricant, a coloring
agent, a buffer, an antioxidant, a surfactant, and the like may be
combined and suitably included in an appropriate amount.
[0073] The term "active component" refers to a material that
exhibits physiological activity included in a pharmaceutical agent,
a quasi-drug, a health food, and the like. The active component
serving as an active component of the three-dimensionally molded
object is not particularly limited as long as it is stable after
thermally melted. For example, the active component maybe a
pharmaceutical. In another embodiment, the active component may be
the one included in a food for specified health uses, a food with
nutrient function claims, a food with function claims, a
supplement, and the like. The pharmaceutically active component
used as the active component is preferably poorly water
soluble.
[0074] However, the pharmaceutically active component is not
particularly limited to the one described above, and may be water
insoluble or water soluble. The pharmaceutically active component
may be an active component included in a food for specified health
uses, a food with nutrient function claims, a food with function
claims, a supplement, and the like.
[0075] The content of the active component of the material for
three-dimensionally molded object (the filament for
three-dimensionally molded object, the three-dimensionally molded
object) is 0.1 to 40 wt. %, preferably 0.1 to 20 wt. %, with
respect to the total weight of the material for three-dimensionally
molded object (the filament for three-dimensionally molded object,
the three-dimensionally molded object). However, the content may be
changed without a particular limitation within a range capable of
achieving the effect of the present invention.
[0076] The term "thermoplastic polymer" refers to a polymer
material which has thermoplasticity, that is, a property causing a
material to be hardly deformable at a normal temperature, but
freely deformable due to plasticity upon appropriate heating and
rigid again upon cooling. The thermoplastic polymer serves as a
base of the three-dimensionally molded object and imparts excellent
injection moldability and printability (plasticity). The
thermoplastic polymer is preferably water soluble in order to
increase elutability of the active component into water.
[0077] Specifically, the thermoplastic polymer is preferably one or
more kinds selected from the group consisting of a polyvinyl
alcohol, a polyvinyl caprolactam-polyvinyl acetate-polyethylene
glycol graft copolymer, polyethylene oxide, polyvinylpyrrolidone,
copolyvidone, a polyethylene glycol-polyvinyl alcohol-graft
copolymer, a polyvinyl alcohol-acrylic acid-methyl methacrylate
copolymer, aminoalkyl methacrylate copolymer RS, and aminoalkyl
methacrylate copolymer E.
[0078] For example, the thermoplastic polymer may be one or more
kinds selected from the group consisting of a polyvinyl alcohol,
polyvinylpyrrolidone, a polyethylene glycol-polyvinyl alcohol-graft
copolymer, and aminoalkyl methacrylate copolymer E. The
thermoplastic polymer is preferably one or more kinds selected from
the group consisting of a polyvinyl alcohol, polyvinylpyrrolidone,
and aminoalkyl methacrylate copolymer E.
[0079] The polyvinyl alcohol is more preferable from the viewpoint
of printability.
[0080] Further, using the polyvinyl alcohol as the thermoplastic
polymer allows the preparation of the filament having high
plasticity and more strength.
[0081] In a case where the polyvinyl alcohol is used as the
water-soluble thermoplastic polymer, the polyvinyl alcohol is
preferably a polymer compound that has high water solubility, a
relatively small average molecular weight (average polymerization
degree), and a relatively small saponification rate.
[0082] Specifically, the polyvinyl alcohol has the average
molecular weight of 20,000 (the average polymerization degree of
400) or less, preferably 10, 000 (the average polymerization degree
of 200) or less, more preferably 6,000 (the average polymerization
degree of 120) or less. Further, the polyvinyl alcohol has the
saponification rate of 90.0 mol % or less, preferably 80.0 mol % or
less.
[0083] The content of the water-soluble thermoplastic polymer is 20
to 90 wt. %, preferably 20 to 80 wt. %, more preferably 20 to 40
wt. %, with respect to the total weight of the material for
three-dimensionally molded object (the filament for
three-dimensionally molded object, the three-dimensionally molded
object). However, the content may be changed without a particular
limitation within a range capable of achieving the effect of the
present invention.
[0084] The term "water-soluble sugar and/or water-soluble sugar
alcohol" refers to a component that imparts excellent plasticity,
improves injection moldability and printability, increases
elutability of the active component into water, and the like.
[0085] For example, the sugar alcohol that hardly causes
caramelization and a Maillard reaction by heat is preferable for
maintaining excellent injection moldability and excellent
extrudability and printability during the three-dimensional
molding. For example, the sugar alcohol may have a glass transition
temperature of a room temperature (1 to 30.degree. C.) or higher,
preferably 40.degree. C. or higher, according to the Japanese
Pharmacopoeia, Sixteenth Edition.
[0086] The "water-soluble sugar and/or water-soluble sugar alcohol"
is desirably one or more kinds of sugar alcohols selected from the
group consisting of maltitol, xylitol, mannitol, erythritol,
sorbitol, isomalt, and lactitol, preferably one or more kinds of
sugar alcohols selected from the group consisting of maltitol,
isomalt, and lactitol. Maltitol is more preferable.
[0087] However, the water-soluble sugar and/or the water-soluble
sugar alcohol may be changed without being particularly limited to
the above within a range capable of achieving the effect of the
present invention. For example, sucrose or the like may be used as
the sugar.
[0088] The content of the water-soluble sugar and/or the
water-soluble sugar alcohol is 10 to 65 wt. %, preferably 10 to 60
wt. %, more preferably 20 to 65 wt. %, further preferably 20 to 60
wt. %, particularly preferably 35 to 55 wt. %, particularly
preferably 20 to 55 wt. %, with respect to the total weight of the
material for three-dimensionally molded object (the filament for
three-dimensionally molded object, the three-dimensionally molded
object). However, the content may be changed without a particular
limitation within a range capable of achieving the effect of the
present invention.
[0089] The term "plasticizer component" refers to a component
serving as a plasticizer in the filament for three-dimensionally
molded object and the three-dimensionally molded object, and the
plasticizer component is added to maintain excellent injection
moldability and printability.
[0090] Specifically, the plasticizer is desirably one or more kinds
selected from the group consisting of triethyl citrate, macrogol,
triacetin, a medium-chain fatty acid triglyceride, a
polyoxyethylene polyoxypropylene block copolymer, and castor oil.
Triethyl citrate is preferable.
[0091] However, the plasticizer component may be changed without
being particularly limited to the above within a range capable of
achieving the effect of the present invention.
[0092] The content of the plasticizer component is 1 to 30 wt. %,
preferably 1 to 10 wt. %, more preferably 1 to 5 wt. %, with
respect to the total weight of the material for three-dimensionally
molded object (the three-dimensionally molded object). However, the
content may be changed without a particular limitation within a
range capable of achieving the effect of the present invention.
[0093] Next, a production method of the three-dimensionally molded
object (the solid object) will be described. Note that the present
invention is not particularly limited to the present production
method.
[0094] The production method of the three-dimensionally molded
object of the present embodiment sequentially performs:
[0095] a material mixing step in which the water-soluble
thermoplastic polymer, the active component, the water-soluble
sugar and/or the water-soluble sugar alcohol, and the plasticizer
component are mixed to obtain the material for three-dimensionally
molded object;
[0096] a compressing and melt-kneading step in which the material
for three-dimensionally molded object is melt-kneaded while being
compressed;
[0097] a filament producing step in which the material for
three-dimensionally molded object, which has been compressed and
melt-kneaded, is subjected to injection molding, and then wound up
with a winder to produce the filament; and
[0098] a molding step in which the filament is thermally melted,
extruded from a nozzle, and laminated on a molding stage to mold
the three-dimensionally molded object.
[0099] That is, in the production method of the three-dimensionally
molded object, first, in the material mixing step, the active
component, the water-soluble thermoplastic polymer, the
water-soluble sugar and/or the water-soluble sugar alcohol, and the
plasticizer component are each mixed in a predetermined formulation
ratio using a mixer to obtain the material for three-dimensionally
molded object.
[0100] Then, the material for three-dimensionally molded object
thus obtained is melt-kneaded while been compressed under a
predetermined pressure using a known extruding machine (e.g., an
extruder) in the compressing and melt-kneading step. After
melt-kneading, injection molding is performed using a molder and an
injection-molded object is wound up with an automatic winder to
obtain the filament for three-dimensionally molded object in the
filament producing step.
[0101] Note that it is desirable that a melting temperature is set
to 120 to 200.degree. C., preferably 140 to 170.degree. C., for
suitably melt-kneading the material for three-dimensionally molded
object in the extruding machine. Further, it is desirable that the
rotation number of barrel is increased to 100 to 200 rpm during
kneading and decreased to 5 to 30 rpm during injection molding.
Further, it is desirable that melt-kneading time is set to 3 to 15
minutes.
[0102] Then, in the molding step, the filament for
three-dimensionally molded object thus obtained is thermally
melted, extruded from a nozzle, and molded while being laminated on
a molding stage using a known fused deposition modeling type 3D
printing apparatus to obtain the three-dimensionally molded
object.
[0103] Note that it is desirable that a nozzle temperature is set
to 80 to 250.degree. C., preferably 110 to 200.degree. C., more
preferably 150.degree. C. or 160.degree. C. or higher and
250.degree. C. or 200.degree. C. or lower, for suitably extruding
the filament for three-dimensionally molded object from the
nozzle.
[0104] As described above, when the three-dimensionally molded
object is produced by using the material for three-dimensionally
molded object (the filament for three-dimensionally molded object)
of the present invention, it becomes possible to form the solid
object that exhibits excellent injection moldability and
printability (plasticity) as well as fast elutability adjusted to
increase the elution rate of the pharmaceutically active
component.
[0105] Here, the term "injection moldability" will be described.
First, the filament for three-dimensionally molded object needs to
be molded into a fixed thickness. A reason for this is that if a
diameter of the molded filament is uneven, an extrusion amount from
the 3D printing apparatus becomes uneven, thereby easily causing a
printing failure. Further, after injection molding, the filament
needs to be solidified relatively quickly. A reason for this is
that the slow solidification results in the filament of uneven
thickness.
[0106] Further, the term "printability" will be described. First,
the filament for three-dimensionally molded object needs to be
inserted into a silicon tube attached to the 3D printing apparatus
for setting the filament to the 3D printing apparatus. This
operation requires the filament to be flexible enough to be bent to
some extent (the filament can be set to the apparatus if the
filament is bendable at least when heated). Further, the filament
needs to have enough plasticity not to be broken when it is
suitably bent to be set to the apparatus. A reason for this is that
if the filament has low plasticity and is thus fragile, a part of
the filament is chipped, thereby causing a gap, which makes it
difficult to perform stable printing. Further, after the filament
is melted at a tip of the nozzle of the 3D printing apparatus, a
melted material needs to be extruded by a fixed amount.
[0107] Using the material for three-dimensionally molded object of
the present invention gives a good result in injection moldability
and printability and makes it possible to form a desired
three-dimensionally molded object.
[0108] Further, the term "three-dimensionally molded object
exhibiting fast elutability" will be described. In the present
invention, according to a paddle method (the paddle rotation
number: 50 rpm) of a dissolution test method in the Japanese
Pharmacopoeia, Sixteenth Edition, the elution rate of the active
component in the solid object is 80% or higher within 120 minutes,
preferably 80% or higher within 85 minutes, more preferably 80% or
higher within 60 minutes, further preferably 80% or higher within
30 minutes, particularly preferably 85% or higher within 30
minutes, particularly preferably 90% or higher within 30 minutes,
particularly preferably 85% or higher within 15 minutes. An upper
limit of the elution rate is 100%. As a test solution used in the
dissolution test, for example, a dissolution test 1st fluid, water,
or the like may be used.
[0109] Using the material for three-dimensionally molded object of
the present invention makes it possible to form a fast-eluting
solid object that quickly elutes the active component.
EXAMPLE
[0110] Examples of the present invention will be described in
detail below. Note that the present invention is not limited to the
present examples.
Example 1
Three-Dimensionally Molded Objects Having Different Formulation
Ratios of Maltitol
[0111] A filament was prepared using a material for
three-dimensionally molded object having a formulation ratio shown
in Table 1 with a extruder equipped with an injection molder,
Xplore (registered trademark, manufactured by DSM) and then a solid
object serving as a three-dimensionally molded object was produced
using a fused deposition modeling type 3D printing apparatus,
Eagleed (registered trademark, manufactured by Reis Enterprise Co.,
Ltd).
[0112] As specific materials,
N.sup.2-[(2E)-3-(4-chlorophenyl)-2-propenoyl]-N-[2-oxo-2-(4-{[6-(trifluor-
omethyl)pyrimidine-4-yl]oxy}piperidine-1-yl)ethyl]-3-pyridine-2-yl-L-alani-
namide (manufactured by Astellas Pharma Inc., a solubility to a
dissolution test 1st fluid of the Japanese Pharmacopoeia: >100
.mu.M, a solubility to a dissolution test 2nd fluid of the Japanese
Pharmacopoeia: 23.2 .mu.M, hereinafter abbreviated as a compound A)
was selected as an active component, Poly(vinyl alcohol) [MW 6000]
(manufactured by Polysciences, Inc., the same hereinafter unless
otherwise specified) was selected as a thermoplastic polymer,
maltitol (SweetPearl P200, manufactured by Roquette, the same
hereinafter unless otherwise specified) was selected as a sugar
alcohol, and Triethyl Citrate (manufactured by Tokyo Chemical
Industry Co., Ltd., the same hereinafter unless otherwise
specified) was selected as a plasticizer component.
[0113] Further, a formulation ratio of maltitol was set to 0 wt. %
in a sample of maltitol 0 wt. % in Comparative example 1-1, a
formulation ratio of maltitol was set to 35 wt. % in a sample of
maltitol 35 wt. % in Example 1-1, and a formulation ratio of
maltitol was set to 55 wt. % in a sample of maltitol 55 wt. % in
Example 1-2 to produce the solid objects (n=2).
[0114] Each solid object in Examples 1-1 and 1-2 and Comparative
example 1-1 was formed in a cylinder shape, and setting values of
3D CAD data were set such that height of each solid object became
1.5 mm and a diameter of each solid object became 12.0 mm.
TABLE-US-00001 TABLE 1 SOLID OBJECTS COMPARATIVE EXAMPLE 1-1
EXAMPLE 1-1 EXAMPLE 1-2 MALTITOL MALTITOL MALTITOL 0 wt. % 35 wt. %
55 wt. % EACH COMPOUND A 20 20 20 CONSTITUENT POLYVINYL 79 40 20
COMPONENT ALCOHOL (wt. %) MALTITOL 0 35 55 TRIETHYL 1 5 5 CITRATE
WEIGHT OF SOLID OBJECT (mg) 208 239 222 Average(n = 2) HEIGHT OF
SOLID OBJECT (mm) 1.6 1.6 1.6 Average(n = 2)
Test Example 1
Elution Test of Active Component
[0115] An elution test was performed using the solid objects in
Examples 1-1 and 1-2 and Comparative example 1-1 shown in Table 1
in accordance with the paddle method (the paddle rotation number:
50 rpm (revolution per minute)) of the dissolution test method in
the Japanese Pharmacopoeia, Sixteenth Edition.
[0116] As a test liquid, 900 ml of the dissolution test 1st fluid
was used and an elution rate of the active component (the compound
A) after starting the test was evaluated by an ultraviolet-visible
spectroscopic method (a UV-VIS method).
[0117] (Results and Discussion of Test Example 1)
[0118] On the basis of analysis of test results, a graph in FIG. 1
shows a relation between "time (min) after starting test" and
"elution rate (%) of active component" of the solid object in each
Example.
[0119] The solid object in Example 1-1 showed an average elution
rate of 87.9% after the lapse of 55 minutes.
[0120] The solid object in Example 1-2 showed an average elution
rate of 87.5% after the lapse of 45 minutes.
[0121] From the results in Test example 1, it was found that
formulation of maltitol caused fast elution. Further, it was found
that increasing the formulation ratio of maltitol caused further
faster elution of the active component.
Example 2
Three-Dimensionally Molded Objects Having Different Shapes
[0122] As the three-dimensionally molded objects having different
shapes, a total of three kinds of the solid objects (n=2) were
produced as follows: a cylinder shape shown in FIG. 2A (Example
2-1), a ring shape 1 shown in FIG. 2B (Example 2-2), and a ring
shape 2 shown in FIG. 2C (Example 2-3).
[0123] A formulation ratio of each constituent component was
adjusted such that the compound A as the active component became 20
wt. %, the polyvinyl alcohol became 20 wt. %, maltitol became 55
wt. %, and triethyl citrate became 5 wt. % with respect to 100 wt.
% of the total weight.
TABLE-US-00002 TABLE 2 SOLID OBJECTS SHAPES EXAMPLE 2-1 EXAMPLE 2-2
EXAMPLE 2-3 OF SOLID CYLINDER RING RING OBJECTS SHAPE SHAPE 1 SHAPE
2 3D CAD DIAMETER 12.0 mm OUTER DIAMETER 12.0 mm OUTERMOST CIRCLE
DATA INNER DIAMETER 7.6 mm OUTER DIAMETER 12.0 mm SETTING OUTERMOST
CIRCLE VALUES INNER DIAMETER 10.0 mm INTERMEDIATE CIRCLE OUTER
DIAMETER 8.0 mm INTERMEDIATE CIRCLE INNER DIAMETER 6.0 mm INNERMOST
CIRCLE OUTER DIAMETER 4.0 mm INNERMOST CIRCLE INNER DIAMETER 2.0 mm
WEIGHT 222 281 263 OF SOLID OBJECT (mg) Average(n = 2) HEIGHT OF
1.6 2.7 2.6 SOLID OBJECT(mm) Average(n = 2)
Test Example 2
Elution Test of Active Component
[0124] The elution test was performed using the solid objects in
Examples 2-1 to 2-3 in the same manner as in Test example 1 in
accordance with the paddle method (the paddle rotation number: 50
rpm) of the dissolution test method in the Japanese Pharmacopoeia,
Sixteenth Edition.
[0125] (Results and Discussion of Test Example 2)
[0126] On the basis of analysis of test results, a graph in FIG. 3
shows a relation between the "time (min) after starting test" and
the "elution rate (%) of active component" of the solid object in
each of Examples 2-1 to 2-3.
[0127] From the results in Test example 2, the solid object formed
in the cylinder shape in Example 2-1 showed the average elution
rate of 87.5% after the lapse of 45 minutes, the solid object
formed in the ring shape 1 in Example 2-2 showed the average
elution rate of 95.3% after the lapse of 20 minutes, and the solid
object formed in the ring shape 2 in Example 2-3 showed the average
elution rate of 94.1% after the lapse of 10 minutes.
[0128] Further, selecting the ring shapes in Examples 2-2 and 2-3
having larger surface areas caused further faster elutability.
Example 3
Three-Dimensionally Molded Object Including 100 mg of Active
Component
[0129] As the three-dimensionally molded object including 100 mg of
the active component, the solid object in Example 3 having a shape
and a formulation ratio shown in Table 3 was produced.
[0130] Note that the ring shape 1 shown in FIG. 2B was selected as
the shape in Example 3 and a formulation ratio of each constituent
component was adjusted such that the compound A as the active
component became 20 wt. %, the polyvinyl alcohol became 20 wt. %,
maltitol became 55 wt. %, and triethyl citrate became 5 wt. % with
respect to 100 wt. % of the total weight.
TABLE-US-00003 TABLE 3 EXAMPLE 3 EACH CONSTITUENT COMPOUND A 20
COMPONENT (wt. %) POLYVINYL ALCOHOL 20 MALTITOL 55 TRIETHYL CITRATE
5 TOTAL (wt. %) 100 3D CAD DATA RING SHAPE 1 SETTING VALUES OUTER
DIAMETER 12.0 mm INNER DIAMETER 7.6 mm WEIGHT OF SOLID OBJECT (mg)
(n = 1) 482 HEIGHT OF SOLID OBJECT (mm) (n = 1) 4.6
Test Example 3
Elution Test of Active Component
[0131] The elution test was performed using the solid object in
Example 3 shown in Table 3 in the same manner as in Test example 1
in accordance with the paddle method (the paddle rotation number:
50 rpm) of the dissolution test method in the Japanese
Pharmacopoeia, Sixteenth Edition.
[0132] (Results and Discussion of Test Example 3)
[0133] On the basis of analysis of results of the elution test, a
graph in FIG. 4 shows a relation between the "time (min) after
starting test" and the "elution rate (%) of active component" of
the solid object in Example 3.
[0134] From the results in Test example 3, the solid object in
Example 3 showed the elution rate of 92.0% after the lapse of 20
minutes.
Test Example 4
Evaluation Test of Oral Absorbability in Dog
[0135] A test for evaluating oral absorbability in a dog was
performed using the solid object in Example 3.
[0136] Specifically, the solid object in Example was used as an
administration sample and the solid object in Example 3 was orally
administered to a dog with a small amount of water. Blood was
collected at a total of 8 time points of 0.25, 0.5, 1, 2, 4, 6, 8,
and 24 hours post oral administration. Subsequently, a drug
concentration in blood plasma obtained by centrifugal separation
was measured using a liquid chromatographic mass spectrometer. Note
that four dogs (n=4) were prepared in the present test.
[0137] Note that, as for intake of food and water, the dogs were
fasted from 16 hours before administration of the solid object in
Example 3 until completion of the blood collection at 8 hours after
administration of the solid object. Further, the dogs were
restricted from water from 30 minutes before administration until
completion of the blood collection at 2 hours after
administration.
[0138] For adjusting pH in stomach, intramuscular administration of
pentagastrin (0.015 mg/kg) was performed at 30 minutes before
administration of the solid object in Example 3, and 30 and 90
minutes after administration of the solid object.
[0139] In a detail of the administration method, water is
administered by a catheter immediately after administration of the
solid object to obtain a total administration liquid amount of up
to 50 ml.
[0140] (Results and Discussion of Test Example 4)
[0141] On the basis of analysis of test results, a graph in FIG. 5
shows a relation between "time (h) after oral administration" and
"concentration in blood plasma (.mu.g/ml)" of the solid object in
Example 3.
[0142] Further, "Cmax (.mu.g/ml)", "Tmax (h)" and "AUC.sup.0-24
(.mu.gh/ml)" were obtained on the basis of the graph in FIG. 5 and
shown in Table 4.
TABLE-US-00004 TABLE 4 EXAMPLE 3 Cmax(.mu.g/ml) 5.6 .+-. 1.8
Tmax(h) 1.2 .+-. 0.8 AUC.sup.0-24(.mu.g h/ml) 35.1 .+-. 11.1
[0143] Note that "Cmax (.mu.g/ml)" represents a maximum
concentration in the blood plasma and "Tmax (h)" represents a time
required for reaching the maximum concentration in the blood plasma
(a time required for reaching Cmax).
[0144] "AUC.sup.0-24 (.mu.gh/ml)" represents an area under the
blood plasma drug concentration-time curve from the time of oral
administration to 24 hours after oral administration.
[0145] In Example 3, Tmax was 1.2.+-.0.8 (h) and AUC was
35.1.+-.11.1 (.mu.gh/ml), thus it could be said that the solid
object of the present invention exhibited a performance of quickly
releasing a drug in vivo.
[0146] From the results in Test examples 1 to 4, it was found that
when the three-dimensionally molded object was prepared using the
material for three-dimensionally molded object (the filament for
three-dimensionally molded object) in each Example of the present
invention, the fast-eluting solid object having excellent injection
moldability and printability (plasticity) could be produced.
Example 4
Three-Dimensionally Molded Objects Including Various Sugars and
Sugar Alcohols
[0147] The filaments having formulation and formulation ratios
shown in Table 5 were produced and the solid objects in Examples
4-1 to 4-8 (n=3) were produced using these filaments with the 3D
printer as the three-dimensionally molded objects each including 50
mg of the active component.
[0148] Note that the ring shape 1 shown in FIG. 2B was selected as
the shape in Examples 4-1 to 4-8 and printing was performed on the
basis of 3D CAD data in which an outer diameter of the ring was set
to 12.0 mm and an inner diameter of the ring was set to 7.6 mm. A
formulation ratio of each constituent component was adjusted such
that the compound A as the active component became 20 wt. %, the
polyvinyl alcohol became 40 wt. %, the water-soluble sugar and/or
the water-soluble sugar alcohol became 35 wt. %, and triethyl
citrate became 5 wt. % with respect to 100 wt. % of the total
weight.
[0149] Note that, as the sugar or the sugar alcohol, other than the
same maltitol as used in Example 1, xylitol (product name: xylitol,
manufactured by Wako Pure Chemical Industries, Ltd.), mannitol
(product name: Pearlitol 200SD, manufactured by Roquette), lactitol
(product name: lactitol monohydrate, manufactured by Wako Pure
Chemical Industries, Ltd.), sucrose (product name: sucrose,
manufactured by Wako Pure Chemical Industries, Ltd.), erythritol
(product name: erythritol 100M, manufactured by B Food Science Co.,
Ltd.), sorbitol (product name: sorbitol, manufactured by KANTO
CHEMICAL Co., Inc.), and isomalt (product name: Galen IQ720,
manufactured by BENEO-Palatinit GmbH) were used.
TABLE-US-00005 TABLE 5 EXAMPLE EXAMPLE EXAMPLE EXAMPLE EXAMPLE
EXAMPLE EXAMPLE EXAMPLE 4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8 MALTITOL
XYLITOL MANNITOL LACTITOL SUCROSE ERYTHRITOL SORBITOL ISOMALT EACH
COMPOUND 20 20 20 20 20 20 20 20 CONSTI- A TUENT POLYVINYL 40 40 40
40 40 40 40 40 COMP- ALCOHOL ONENT MALTITOL 35 -- -- -- -- -- -- --
(wt. %) XYLITOL -- 35 -- -- -- -- -- -- MANNITOL -- -- 35 -- -- --
-- -- LACTITOL -- -- -- 35 -- -- -- -- SUCROSE -- -- -- -- 35 -- --
-- ERYTHRITOL -- -- -- -- -- 35 -- -- SORBITOL -- -- -- -- -- -- 35
-- ISOMALT -- -- -- -- -- -- -- 35 TRIETHYL 5 5 5 5 5 5 5 5 CITRATE
WEIGHT OF SOLID 246 263 262 238 261 256 263 248 OBJECT (mg) Average
(n = 3) HEIGHT OF SOLID 2.6 2.7 2.7 2.4 2.6 2.6 2.5 2.7 OBJECT (mm)
Average (n = 3)
Test Example 5
Elution Test of Active Component
[0150] The elution test was performed using the solid objects in
Examples 4-1 to 4-8 in the same manner as in Test example 1 in
accordance with the paddle method (the paddle rotation number: 50
rpm) of the dissolution test method in the Japanese Pharmacopoeia,
Sixteenth Edition.
[0151] (Results and Discussion of Test Example 5)
[0152] On the basis of analysis of results of the elution test, a
graph in FIG. 6 shows a relation between the "time (min) after
starting test" and the "elution rate (%) of active component" of
the solid object in each of Examples 4-1 to 4-8.
[0153] From the results in Test example 5, the solid objects in
Examples 4-1 to 4-8 showed the elution rates after the lapse of 30
minutes as follows: 91% (Example 4-1: maltitol), 95% (Example 4-2:
xylitol), 93% (Example 4-3: mannitol), 85% (Example 4-4: lactitol),
93% (Example 4-5: sucrose), 90% (Example 4-6: erythritol), 80%
(Example 4-7: sorbitol), and 92% (Example 4-8: isomalt).
Example 5
Three-Dimensionally Molded Objects Including Different Active
Components
[0154] The filaments having formulation and formulation ratios
shown in Table 6 were produced and the solid objects in Examples
5-1 and 5-2 (n=3) were produced with the 3D printer as the
three-dimensionally molded objects each including 50 mg of the
active component. In Example 5-1, acetaminophen (product name:
pharmacopoeia acetaminophen, manufactured by YAMAMOTO Corp.) was
formulated as the active component and, in Example 5-2,
theophylline (product name: Theophylline, manufactured by Tokyo
Chemical Industry Co., Ltd.) was formulated as the active
component.
[0155] Note that the ring shape 1 shown in FIG. 2B was selected as
the shape in Examples 5-1 and 5-2 and printing was performed on the
basis of 3D CAD data in which an outer diameter of the ring was set
to 12.0 mm and an inner diameter of the ring was set to 7.6 mm. A
formulation ratio of each constituent component was adjusted such
that the active component became 20 wt. %, the polyvinyl alcohol
became 40 wt. %, maltitol became 35 wt. %, and triethyl citrate
became 5 wt. % with respect to 100 wt. % of the total weight.
TABLE-US-00006 TABLE 6 EXAMPLE 5-1 EXAMPLE 5-2 ACETAMINOPHEN
THEOPHYLLINE EACH ACETAMINOPHEN 20 -- CONSTITUENT THEOPHYLLINE --
20 COMPONENT POLYVINYL ALCOHOL 40 40 (wt. %) MALTITOL 35 35
TRIETHYL CITRATE 5 5 WEIGHT OF SOLID OBJECT (mg) 267 252 Average(n
= 3) HEIGHT OF SOLID OBJECT (mm) 2.7 2.4 Average(n = 3)
Test Example 6
Elution Test of Active Component
[0156] The elution test was performed using the solid objects in
Examples 5-1 and 5-2 in the same manner as in Test example 1 in
accordance with the paddle method (the paddle rotation number: 50
rpm) of the dissolution test method in the Japanese Pharmacopoeia,
Sixteenth Edition.
[0157] (Results and Discussion of Test Example 6)
[0158] On the basis of analysis of results of the elution test, a
graph in FIG. 7 shows a relation between the "time (min) after
starting test" and the "elution rate (%) of active component" of
the solid object in each of Examples 5-1 and 5-2.
[0159] From the results in Test example 6, the solid objects in
Examples 5-1 and 5-2 showed the elution rates after the lapse of
minutes of 97% (acetaminophen) and 91% (theophylline),
respectively, confirming that the present invention could be
applied to an active component other than the compound A.
Comparative Example 1
Comparison with Three-dimensionally Molded Object Including
Insoluble Component
[0160] The filaments having formulation and formulation ratios
shown in Table 7 were produced using tricalcium phosphate or talc
as an insoluble component instead of the sugar and/or the sugar
alcohol of the present invention, and the solid objects in
Comparative examples 2-1 and 2-2 (n=3) were produced with the 3D
printer as the three-dimensionally molded objects each including 50
mg of the active component.
[0161] Note that the ring shape 1 shown in FIG. 2B was selected as
the shape in Comparative examples 2-1 and 2-2 and printing was
performed on the basis of 3D CAD data in which an outer diameter of
the ring was set to 12.0 mm and an inner diameter of the ring was
set to 7.6 mm. A formulation ratio of each constituent component
was adjusted such that the compound A as the active component
became 20 wt. %, the polyvinyl alcohol became 40 wt. %, tricalcium
phosphate (product name: tricalcium phosphate food additives,
manufactured by KANTO CHEMICAL Co., Inc.) or talc (product name:
crown talc pharmacopoeia PP, manufactured by matsumura sangyo Co.,
Ltd.) became 35 wt. %, and triethyl citrate became 5 wt. % with
respect to 100 wt. % of the total weight.
TABLE-US-00007 TABLE 7 COMPARATIVE EXAMPLE 2-1 COMPARATIVE
TRICALCIUM EXAMPLE 2-2 PHOSPHATE TALC EACH COMPOUND A 20 20
CONSTITUENT POLYVINYL ALCOHOL 40 40 COMPONENT TRICALCIUM PHOSPHATE
35 -- (wt. %) TALC -- 35 TRIETHYL CITRATE 5 5 WEIGHT OF SOLID
OBJECT (mg) 264 256 Average(n = 3) HEIGHT OF SOLID OBJECT (mm) 2.4
2.1 Average(n = 3)
Test Example 7
Elution Test of Active Component
[0162] The elution test was performed using the solid objects in
Comparative examples 2-1 and 2-2 shown in Table 7 in the same
manner as in Test example 1 in accordance with the paddle method
(the paddle rotation number: 50 rpm) of the dissolution test method
in the Japanese Pharmacopoeia, Sixteenth Edition.
[0163] (Results and Discussion of Test Example 7)
[0164] On the basis of analysis of results of the above-mentioned
elution test, a graph in FIG. 8 shows a relation between the "time
(min) after starting test" and the "elution rate (%) of active
component" of the solid object in each of Comparative examples 2-1
and 2-2.
[0165] From the results in Test example 7, it was found that the
solid objects in Comparative examples 2-1 and 2-2 showed the
elution rates after the lapse of 30 minutes of 63% (Comparative
example 2-1: tricalcium phosphate) and 60% (Comparative example
2-2: talc), both values being lower than 80%.
[0166] Thus, it was confirmed that a formulation having a higher
elution rate could be prepared by adding the sugar and/or the sugar
alcohol as compared to the case where tricalcium phosphate or talc
was included.
Example 6
Three-Dimensionally Molded Object Having Different Formulation
Ratio of Maltitol
[0167] The filament of Example 6 having formulation and a
formulation ratio shown in Table 8 was produced and the solid
objects (n=3) were produced with the 3D printer.
[0168] Note that the ring shape 1 shown in FIG. 2B was selected as
the shape in Example 6 and printing was performed on the basis of
3D CAD data in which an outer diameter of the ring was set to 12.0
mm and an inner diameter of the ring was set to 7.6 mm. A
formulation ratio of each constituent component was adjusted such
that the compound A as the active component became 20 wt. %, the
polyvinyl alcohol became 55 wt. %, maltitol became 20 wt. %, and
triethyl citrate became 5 wt. % with respect to 100 wt. % of the
total weight.
TABLE-US-00008 TABLE 8 EXAMPLE 6 MALTITOL 20 wt. % EACH COMPOUND A
20 CONSTITUENT POLYVINYL ALCOHOL 55 COMPONENT MALTITOL 20 (wt. %)
TRIETHYL CITRATE 5 WEIGHT OF SOLID OBJECT (mg) 229 Average(n = 3)
HEIGHT OF SOLID OBJECT (mm) 2.4 Average(n = 3)
Test Example 8
Elution Test of Active Component
[0169] The elution test was performed using the solid object in
Example 6 shown in Table 8 in the same manner as in Test example 1
in accordance with the paddle method (the paddle rotation number:
50 rpm) of the dissolution test method in the Japanese
Pharmacopoeia, Sixteenth Edition.
[0170] (Results and Discussion of Test Example 8)
[0171] On the basis of analysis of results of the above elution
test, a graph in FIG. 9 shows a relation between the "time (min)
after starting test" and the "elution rate (%) of active component"
of the solid object in Example 6.
[0172] From the result in Test example 8, it was confirmed that the
solid object in Example 6 showed the elution rate after the lapse
of 30 minutes of 80%. It was found that the elution rate increased
by an increase in the addition amount of maltitol by comparing the
elution rates obtained with the above formulation, the formulation
in Example 2-2 in which maltitol was added in the amount of 55 wt.
%, and the formulation in Example 4-1 in which maltitol was added
in the amount of 35 wt. %.
Example 7
Three-Dimensionally Molded Objects Including Different
Thermoplastic Polymers
[0173] The filaments in Examples 7-1 and 7-2 having formulation and
formulation ratios shown in Table 9 were produced by selecting
polyvinylpyrrolidone (Polyvinylpyrrolidone [Mw40000], manufactured
by Sigma Aldrich) or aminoalkyl methacrylate copolymer E (Eudragit
EPO, manufactured by Evonik Industries AG) instead of the polyvinyl
alcohol as the thermoplastic polymer. A formulation ratio of each
constituent component was adjusted such that the compound A as the
active component became 20 wt. %, the thermoplastic polymer became
40 wt. %, maltitol became 35 wt. %, and triethyl citrate became 5
wt. % with respect to 100 wt. % of the total weight.
[0174] The filament produced by using polyvinylpyrrolidone tended
to be more fragile as compared to the one produced by using the
polyvinyl alcohol.
TABLE-US-00009 TABLE 9 EXAMPLE 7-2 AMINOALKYL EXAMPLE 7-1
METHACRYLATE POLYVINYLPYRROLIDONE COPOLYMER E EACH COMPOUND A 20 20
CONSTITUENT POLYVINYLPYRROLIDONE 40 -- COMPONENT AMINOALKYL
METHACRYLATE -- 40 (wt. %) COPOLYMER E MALTITOL 35 35 TRIETHYL
CITRATE 5 5
Test Example 9
Elution Test of Active Component
[0175] The elution test was performed using the filaments in
Examples 7-1 and 7-2 shown in Table 9, the filament including the
polyvinyl alcohol and maltitol produced in Example 4-1, and the
filament including the polyvinyl alcohol and tricalcium phosphate
produced in Comparative example 2-1 in the same manner as in Test
example 1 in accordance with the paddle method (the paddle rotation
number: 50 rpm) of the dissolution test method in the Japanese
Pharmacopoeia, Sixteenth Edition.
[0176] Note that each filament in use included the compound A
having a weight of 50 mg as the active component.
[0177] (Results and Discussion of Test Example 9)
[0178] On the basis of analysis of results of the elution test, a
graph in FIG. 10 shows a relation between the "time (min) after
starting test" and the "elution rate (%) of active component" of
the filament in each of Examples 4-1, 7-1, and 7-2, and Comparative
example 2-1.
[0179] From the results in Test example 9, the filaments in
Examples 7-1 and 7-2 showed the elution rates after the lapse of 5
minutes of 100% (Example 7-1: polyvinylpyrrolidone) and 91%
(Example 7-2: aminoalkyl methacrylate copolymer E) . The filament
including the polyvinyl alcohol and maltitol in Example 4-1 and the
filament including the polyvinyl alcohol and tricalcium phosphate
in Comparative example 2-1 had the elution rates after the lapse of
5 minutes of 44% and 25%, respectively, thus it was found that the
fast elutability was exhibited in the formulation in Examples 7-1
and 7-2 in which polyvinylpyrrolidone and aminoalkyl methacrylate
copolymer E were used.
Solid Object in Example 7-1: Three-Dimensionally Molded Object
Using Polyvinylpyrrolidone
[0180] The solid objects in Example 7-1 (n=3) were produced with
the 3D printer using the filament produced in Example 7-1.
[0181] Note that the ring shape 1 shown in FIG. 2B was selected as
the shape of the solid object in Example 7-1 and printing was
performed on the basis of 3D CAD data in which an outer diameter of
the ring was set to 12.0 mm and an inner diameter of the ring was
set to 7.6 mm. A weight of a printed object and a height of the
solid object were shown in Table 10.
TABLE-US-00010 TABLE 10 EXAMPLE 7-1 POLYVINYLPYRROLIDONE/ MALTITOL
35% WEIGHT OF SOLID OBJECT (mg) 249 Average(n = 3) HEIGHT OF SOLID
OBJECT (mm) 2.5 Average(n = 3)
Test Example 10
Elution Test of Active Component
[0182] The elution test was performed using the solid object in
Example 7-1 in the same manner as in Test example 1 in accordance
with the paddle method (the paddle rotation number: 50 rpm) of the
dissolution test method in the Japanese Pharmacopoeia, Sixteenth
Edition.
[0183] (Results and Discussion of Test Example 10)
[0184] On the basis of analysis of results of the elution test, a
graph in FIG. 11 shows a relation between the "time (min) after
starting test" and the "elution rate (%) of active component" of
the solid object in Example 7-1. FIG. 11 also showed the graph of
the solid object in Example 4-1.
[0185] From the results in Test example 10, it was confirmed that
the solid object in Example 7-1 showed the elution rate after the
lapse of 30 minutes of 99%.
INDUSTRIAL APPLICABILITY
[0186] The three-dimensionally molded object of the present
invention can be suitably used as various molded objects for a
pharmaceutical agent, a quasi-drug, a health food, a food for
specified health uses, a food with nutrient function claims, a food
with function claims, and a supplement, and thus has an industrial
applicability.
* * * * *