U.S. patent application number 15/926054 was filed with the patent office on 2018-07-26 for plastic container comprising cyclic polyolefin layer.
The applicant listed for this patent is Mitsubishi Tanabe Pharma Corporation. Invention is credited to Munetomo Matsuda, Tetsurou Nishimura, Kazuhiko Ozaki, Kenjirou Takayanagi.
Application Number | 20180207131 15/926054 |
Document ID | / |
Family ID | 40667574 |
Filed Date | 2018-07-26 |
United States Patent
Application |
20180207131 |
Kind Code |
A1 |
Ozaki; Kazuhiko ; et
al. |
July 26, 2018 |
PLASTIC CONTAINER COMPRISING CYCLIC POLYOLEFIN LAYER
Abstract
The present invention provides and a plastic container and
multilayered films, which comprises a heat-sealable seal layer, a
cyclic polyolefin layer, and an outermost layer, wherein the seal
layer comprises polypropylene, the cyclic polyolefin layer
comprises a cyclic polyolefin polymer or a cyclic polyolefin
copolymer, and the outermost layer comprises a layer containing
polypropylene, and which further comprises a resin composition
layer comprises a blended product of a propylene polymer and a
styrene elastomer. The plastic container of the present invention
can suppresses a reduction in the medicament content of a
liquid-state medicament and is excellent in terms of shock
resistance, handling ability during the filling of the container
with the medicament, and the moldability and transparency of the
container.
Inventors: |
Ozaki; Kazuhiko; (Osaka-shi,
JP) ; Matsuda; Munetomo; (Osaka-shi, JP) ;
Nishimura; Tetsurou; (Osaka-shi, JP) ; Takayanagi;
Kenjirou; (Yokkaichi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mitsubishi Tanabe Pharma Corporation |
Osaka-shi |
|
JP |
|
|
Family ID: |
40667574 |
Appl. No.: |
15/926054 |
Filed: |
March 20, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12955776 |
Nov 29, 2010 |
9956203 |
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15926054 |
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12744208 |
Sep 1, 2010 |
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PCT/JP2008/071197 |
Nov 21, 2008 |
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12955776 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
3/08 20180101; B32B 2439/80 20130101; B32B 27/302 20130101; B32B
2307/30 20130101; B32B 2250/24 20130101; B32B 2307/308 20130101;
A61P 39/06 20180101; B32B 27/32 20130101; B32B 2270/00 20130101;
B32B 2307/51 20130101; A61K 9/0019 20130101; B32B 2307/412
20130101; B32B 2307/50 20130101; B32B 2307/7265 20130101; A61J 1/10
20130101; A61K 31/4152 20130101; A61P 25/28 20180101; Y10T 428/2826
20150115; A61P 1/04 20180101; B32B 2307/7242 20130101; B32B
2307/546 20130101; B32B 27/325 20130101; B32B 2307/558 20130101;
B32B 27/08 20130101; B32B 2307/31 20130101 |
International
Class: |
A61K 31/4152 20060101
A61K031/4152; B32B 27/32 20060101 B32B027/32; B32B 27/30 20060101
B32B027/30; B32B 27/08 20060101 B32B027/08 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 22, 2007 |
JP |
2007-303568 |
Claims
1-19. (canceled)
20. A pharmaceutical formulation in a unit dosage form comprising
3-methyl-1-phenyl-2-pyrazolin-5-one; wherein the unit dosage form
is a solution stored in a plastic container, and wherein the
container comprises: a multilayered film having six or more layers,
wherein the six or more layers are: an innermost heat-sealable seal
layer consisting essentially of polypropylene, a first resin
composition layer disposed on the innermost heat-sealable seal
layer consisting essentially of a resin composition comprising a
blended product of a propylene polymer and a styrene elastomer, a
cyclic polyolefin barrier layer disposed on the first resin
composition layer consisting of a polymer consisting of repeating
units represented by the formula (1) and repeating units
represented by the formula (1'): ##STR00006## wherein each of Ra,
Ra', Rb and Rb', identically or differently, represents a hydrogen,
a hydrocarbon residue, a halogen, an ester, a nitrile or a pyridyl;
or Ra and Rb may bind to one another to form a ring; or Ra' and Rb'
may bind to one another to form a ring; each of m and m' represents
an integer of 1 or greater; and each of n and n' represents an
integer of 0 or 1 or greater, two or more additional resin
composition layers disposed on the cyclic polyolefin barrier layer
consisting essentially of a resin composition comprising a blended
product of a propylene polymer and a styrene elastomer, and an
outermost layer disposed on the additional resin composition layers
consisting essentially of a polypropylene layer; wherein the
plastic container is molded by heat sealing peripheral portions of
the multilayered films.
21. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the cyclic polyolefin barrier layer has a
glass transition temperature (Tg) of 80.degree. C. to 120.degree.
C.
22. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the melt flow rate (230.degree. C., 21.2 N)
value of the cyclic polyolefin barrier layer is 1 to 20 (g/10
minutes).
23. The pharmaceutical formulation in a unit dosage form according
to claim 22, wherein the melt flow rate (230.degree. C., 21.2 N)
value of the seal layer and/or the outermost layer is 1 to 4 (g/10
minutes).
24. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the maximum fusion peak temperature of the
seal layer is 125.degree. C. to 135.degree. C.
25. The pharmaceutical formulation in a unit dosage form according
to claim 24, wherein the highest fusion peak temperature of the
seal layer is 150.degree. C. to 160.degree. C.
26. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the fusion peak temperature of the outermost
layer is 160.degree. C. to 170.degree. C.
27. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the plastic container can be sterilized at
115.degree. C. for 30 minutes or more.
28. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the plastic container can be sterilized at
121.degree. C. for 15 minutes or more.
29. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the plastic container is in the form of an
infusion bag.
30. The pharmaceutical formulation in a unit dosage form according
to claim 29, wherein the plastic container can be sterilized at
115.degree. C. for 30 minutes or more.
31. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the unit dosage form comprises 30 mg of
3-methyl-1-phenyl-2-pyrazolin-5-one.
32. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the 3-methyl-1-phenyl-2-pyrazolin-5-one is
contained in a concentration of 0.06 mg/mL or higher to 2 mg/mL or
lower.
33. The pharmaceutical formulation in a unit dosage form according
to claim 32, wherein the 3-methyl-1-phenyl-2-pyrazolin-5-one is
contained in a concentration of 0.1 mg/mL or higher to 0.6 mg/mL or
lower.
34. The pharmaceutical formulation in a unit dosage form according
to claim 33, wherein the 3-methyl-1-phenyl-2-pyrazolin-5-one is
contained in a concentration of about 0.3 mg/mL.
35. The pharmaceutical formulation in a unit dosage form according
to claim 20, wherein the 3-methyl-1-phenyl-2-pyrazolin-5-one is
contained in an injection solution.
36. The pharmaceutical formulation in a unit dosage form according
to claim 35, wherein the injection solution is saline.
Description
TECHNICAL FIELD
[0001] The present invention relates to a plastic container
suitable for containing a liquid-state medicament and a
multilayered film used for this container.
BACKGROUND ART
[0002] A reduction in the content of a certain kind of medicament
is suppressed using a container composed of cyclic polyolefin. The
suppression of a reduction in the content of a certain kind of
medicament is disclosed in JP Patent Publication (Kokai) No.
5-293159 A (1993) (Patent Document 1) and JP Patent Publication
(Kokai) No. 2003-24415 A (Patent Document 2), for example. However,
cyclic polyolefin is rigid and fragile, and further, it is poor in
terms of heat-sealing properties. Thus, cyclic polyolefin has been
problematic in that a practical bag cannot be directly formed with
the cyclic polyolefin itself. In order to solve this problem, JP
Patent Publication (Kokai) No. 2002-301796 A (Patent Document 3)
and JP Patent Publication (Kohyo) No. 2005-525952 A (Patent
Document 4), for example, have proposed a multilayered film
comprising a specific ethylene-.alpha.-olefin copolymer and cyclic
polyolefin and a container constituted with the same.
[0003] Moreover, if a constituted multilayered film is rigid and
inflexible, it causes problems such as low shock resistance and
poor handling ability during the filling of a container with a
medicament.
[0004] On the other hand, it has been known that a pyrazolone
derivative represented by the formula (I) as shown below has, as a
medical use, an action to normalize brain function (Patent Document
5; JP Patent Publication (Kokoku) No. 5-31523 B (1993)), an action
to suppress generation of lipid peroxide (Patent Document 6; JP
Patent Publication (Kokoku) No. 5-35128 B (1993); the compound of
Example 1), an antiulcer action (Patent Document 7; JP Patent
Publication (Kokai) No. 3-215425 A (1991)), an action to suppress
an increase in blood sugar (Patent Document 8; JP Patent
Publication (Kokai) No. 3-215426 A (1991)), and the like:
##STR00001##
(wherein R.sup.1 represents a hydrogen atom, an aryl, an alkyl
containing 1 to 5 carbon atoms, or an alkoxycarbonylalkyl
containing 3 to 6 carbon atoms in total; R.sup.2 represents a
hydrogen atom, an aryloxy, an arylmercapto, an alkyl containing 1
to 5 carbon atoms, or a hydroxyalkyl containing 1 to 3 carbon
atoms; or R.sup.1 and R.sup.2 together represent an alkylene
containing 3 to 5 carbon atoms; R.sup.3 represents a hydrogen atom,
an alkyl containing 1 to 5 carbon atoms, a cycloalkyl containing 5
to 7 carbon atoms, a hydroxyalkyl containing 1 to 3 carbon atoms, a
benzyl, naphthyl or phenyl, or a phenyl substituted with 1 to 3
identical or different substituents selected from the group
consisting of an alkoxy containing 1 to 5 carbon atoms, a
hydroxyalkyl containing 1 to 3 carbon atoms, an alkoxycarbonyl
containing 2 to 5 carbon atoms in total, an alkylmercapto
containing 1 to 3 carbon atoms, an alkylamino containing 1 to 4
carbon atoms, a dialkylamino containing 2 to 8 carbon atoms in
total, a halogen atom, a trifluoromethyl, a carboxyl, a cyano, a
hydroxyl group, a nitro, an amino, and an acetamide).
[0005] Moreover, since June 2001, the compound represented by the
formula (I) has been commercially available as a brain-protecting
agent (generic name: "Edaravone"; product name: "Radicut";
manufactured and distributed by Mitsubishi Tanabe Pharma
Corporation). This "Edaravone" has been reported to have high
reactivity with active oxygen (Non-Patent Documents 1 and 2). Thus,
Edaravone is a free radical scavenger that acts to scavenge various
types of free radicals including active oxygen as a typical
example, so as to prevent cell injury.
[0006] At present, Radicut is commercially available as a Radicut
injection 30 mg in the form of a 20 ml of solution containing 30 mg
of 3-methyl-1-phenyl-2-pyrazoline-5-one (Edaravone) filled into a
glass ampule. Furthermore, International Publication WO2007/55312
(Patent Document 9) reports a plastic container filled with an
aqueous solution containing Edaravone, coloration of which is
suppressed. However, a plastic container capable of suppressing a
reduction in the content of Edaravone due to adhesion of Edaravone
to the plastic container has not yet been disclosed. [0007] [Patent
Document 1] JP Patent Publication (Kokai) No. 5-293159 A (1993)
[0008] [Patent Document 2] JP Patent Publication (Kokai) No.
2003-24415 A [0009] [Patent Document 3] JP Patent Publication
(Kokai) No. 2002-301796 A [0010] [Patent Document 4] JP Patent
Publication (Kohyo) No. 2005-525952 A [0011] [Patent Document 5] JP
Patent Publication (Kokoku) No. 5-31523 B (1993) [0012] [Patent
Document 6] JP Patent Publication (Kokoku) No. 5-35128 B (1993)
[0013] [Patent Document 7] JP Patent Publication (Kokai) No.
3-215425 A (1991) [0014] [Patent Document 8] JP Patent Publication
(Kokai) No. 3-215426 A (1991) [0015] [Non-Patent Document 1] Kawai,
H., et al., J. Pharmacol. Exp. Ther., 281(2), 921, 1997 [0016]
[Non-Patent Document 2] Wu, T W. et al., 67(19), 2387, 2000 [0017]
[Patent Document 9] International Publication WO2007/55312
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0018] It is an object of the present invention to provide a
plastic container which suppresses a reduction in the content of a
liquid-state medicament and is excellent in terms of shock
resistance, handling ability during the filling of the container
with the medicament, and the moldability and transparency of the
container, and a multilayered film used for the aforementioned
container.
Means for Solving the Problems
[0019] The multilayered film of the present invention for achieving
the aforementioned object comprises a heat-sealable seal layer, a
cyclic polyolefin layer, and an outermost layer, wherein the seal
layer comprises polypropylene, the cyclic polyolefin layer
comprises a cyclic polyolefin polymer or a cyclic polyolefin
copolymer, and the outermost layer comprises a layer containing
polypropylene, and the present multilayered film further comprises
a resin composition layer comprising a blended product of a
propylene polymer and a styrene elastomer. However, the
multilayered film of the present invention excludes a five-layered
plastic film only composed of a seal layer-an adhesive layer-a
barrier layer-an adhesive layer-a material layer, wherein each of
the seal layer and the material layer consists of only a
polypropylene elastomer having a melting point of 165.degree. C.,
each of the adhesive layers consists of only MODIC manufactured by
Mitsubishi Chemical Corporation, and the barrier layer consists of
only a cyclic polyolefin polymer having a glass transition
temperature of 136.degree. C.
[0020] Moreover, the plastic container according to the present
invention for achieving the aforementioned object is molded by
heat-sealing the peripheral portions of the multilayered films
which comprise a heat-sealable seal layer, a cyclic polyolefin
layer, and an outermost layer wherein the seal layer comprises
polypropylene, the cyclic polyolefin layer comprises a cyclic
polyolefin polymer or a cyclic polyolefin copolymer, and the
outermost layer comprises a layer containing polypropylene, and
which further comprises a resin composition layer comprising a
blended product of a propylene polymer and a styrene elastomer, in
a state in which the seal layers are laminated on each other such
that they face each other. The plastic film of the present
invention is molded, so that the seal layer thereof becomes the
inner surface thereof. Specifically, the seal layer is allowed to
directly come into contact with a liquid-state medicament which is
contained in this container.
[0021] The plastic container or multilayered film according to the
present invention preferably comprises a resin composition layer or
a polyethylene layer on the surfaces of both sides of the cyclic
polyolefin layer. In addition, for such resin composition layer, a
resin composition having a fusion peak temperature only in a
temperature range from 120.degree. C. or higher to 170.degree. C.
or lower and also having a heat of fusion from 5 J/g or more to 20
J/g or less is preferably used.
[0022] The cyclic polyolefin in the cyclic polyolefin layer used
for the plastic container or multilayered film according to the
present invention is preferably a ring-opening polymer
hydrogenation product of dicyclopentadiene or a derivative thereof.
Moreover, another preferred embodiment of the cyclic polyolefin is
cyclic polyolefin having a glass transition temperature (Tg) of
80.degree. C. to 120.degree. C. A further preferred embodiment of
the cyclic polyolefin is cyclic polyolefin having a melt flow rate
(230.degree. C., 21.2 N) value of 1 to 20 (g/10 minutes).
[0023] As a seal layer used for the plastic container or
multilayered film according to the present invention, polypropylene
having a melt flow rate (230.degree. C., 21.2 N) value of 1 to 4
(g/10 minutes) is preferable. Furthermore, another preferred
embodiment of the seal layer is a seal layer having a bending
elasticity of 400 to 600 MPa. A further preferred embodiment of the
seal layer is polypropylene having the maximum fusion peak
temperature of 125.degree. C. to 135.degree. C. A still further
preferred embodiment of the seal layer is propylene having the
highest fusion peak temperature of 150.degree. C. to 160.degree. C.
The maximum fusion peak temperature and the highest fusion peak
temperature used in the present specification will be described.
There are cases in which multiple endothermic peaks are observed in
differential scanning calorimetry (DSC). The maximum fusion peak
temperature means a temperature at which the largest endothermic
peak is observed, and the highest fusion peak temperature means a
temperature at which the highest temperature peak is observed in a
temperature range in which such endothermic peaks are observed.
[0024] The outermost layer used for the plastic container or
multilayered film according to the present invention is preferably
polypropylene having a melt flow rate (230.degree. C., 21.2 N)
value of 1 to 4 (g/10 minutes). Another preferred embodiment of the
outermost layer is polypropylene having a bending elasticity of 400
to 600 MPa. A further preferred embodiment of the outermost layer
is polypropylene having a fusion peak temperature of 160.degree. C.
to 170.degree. C.
[0025] In the present invention, a multilayered film having a
tensile elasticity of 300 MPa or less and a plastic container
molded using this multilayered film are preferable.
[0026] The plastic container according to the present invention can
be preferably sterilized at 115.degree. C. for 30 minutes or more.
In another preferred embodiment, the plastic container according to
the present invention can be sterilized at 121.degree. C. for 15
minutes or more.
[0027] The active ingredient of a liquid-state medicament placed in
the plastic container according to the present invention is
preferably a pyrazolone derivative represented by the formula (I)
as shown below, a physiologically acceptable salt thereof, a
hydrate thereof, or a solvate thereof:
##STR00002##
(wherein R.sup.1 represents a hydrogen atom, an aryl, an alkyl
containing 1 to 5 carbon atoms, or an alkoxycarbonylalkyl
containing 3 to 6 carbon atoms in total; R.sup.2 represents a
hydrogen atom, an aryloxy, an arylmercapto, an alkyl containing 1
to 5 carbon atoms, or a hydroxyalkyl containing 1 to 3 carbon
atoms; or R.sup.1 and R.sup.2 together represent an alkylene
containing 3 to 5 carbon atoms; R.sup.3 represents a hydrogen atom,
an alkyl containing 1 to 5 carbon atoms, a cycloalkyl containing 5
to 7 carbon atoms, a hydroxyalkyl containing 1 to 3 carbon atoms, a
benzyl, naphthyl or phenyl, or a phenyl substituted with 1 to 3
identical or different substituents selected from the group
consisting of an alkoxy containing 1 to 5 carbon atoms, a
hydroxyalkyl containing 1 to 3 carbon atoms, an alkoxycarbonyl
containing 2 to 5 carbon atoms in total, an alkylmercapto
containing 1 to 3 carbon atoms, an alkylamino containing 1 to 4
carbon atoms, a dialkylamino containing 2 to 8 carbon atoms in
total, a halogen atom, a trifluoromethyl, a carboxyl, a cyano, a
hydroxyl group, a nitro, an amino, and an acetamide). In another
preferred embodiment, the active ingredient of a liquid-state
medicament is 3-methyl-1-phenyl-2-pyrazolin-5-one.
[0028] The plastic container according to the present invention is
preferably in the form of an infusion bag.
[0029] Moreover, the plastic container according to the present
invention is preferably placed together with an oxygen absorber
into a poorly air-permeable container.
[0030] When the active ingredient of a liquid-state medicament
placed in the plastic container according to the present invention
is the pyrazolone derivative represented by the above-described
formula (I), a physiologically acceptable salt thereof, a hydrate
thereof, or a solvent thereof, a reduction percentage in the
content of the active ingredient after the preservation thereof at
60.degree. C. for 4 weeks is preferably 4% or less. On the other
hand, a reduction percentage in the content of the active
ingredient after sterilization is preferably 4% or less.
BEST MODE FOR CARRYING OUT THE INVENTION
[0031] The plastic container and the multilayered film provided by
the present invention have a structure in which they comprise at
least a cyclic polyolefin layer and a resin composition layer
between an outermost layer and a seal layer. The disposition is not
limited. Preferably, the resin composition layers or the
polyethylene layers are disposed on both sides of the cyclic
polyolefin layer. More preferably, the resin composition layers are
disposed on both sides of the cyclic polyolefin layer. The resin
composition layer that can be disposed on the outermost layer side
of this cyclic polyolefin layer may be identical to or different
from the resin composition layer that can be disposed on the seal
layer side thereof. The same applies to the polyethylene layer.
[0032] Polyethylene that constitutes the polyethylene layer used in
the present invention may be a copolymer of ethylene with
.alpha.-olefin such as propylene, 1-butene, 4-methyl-1-pentene or
1-octene, as well as an ethylene homopolymer. In addition, the
above-mentioned copolymer may be either a linear or branched
copolymer. Moreover, a mixed resin of the ethylene homopolymer and
the above-mentioned .alpha.-olefin may also be used. Furthermore,
regardless of whether it is high-density or low-density, such
polyethylene can be selected from a wide range of polyethylenes, as
appropriate. From the viewpoint of flexibility and transparency,
linear low-density polyethylene is advantageously used.
[0033] Specific examples of polyethylene preferably used in the
present invention include an ethylene homopolymer (product name:
HARMOREC (registered trademark)), an .alpha.-olefin copolymer
(product name: TOUGHMER (registered trademark)), and an
ethylene-1-octene copolymer (product name: MORETEC (registered
trademark)). A more preferred example of polyethylene is a mixed
resin of HARMOREC (registered trademark) and TOUGHMER (registered
trademark).
[0034] The thickness of this polyethylene layer is not particularly
limited. It is preferably from 10 .mu.m or more to 150 .mu.m or
less.
[0035] A resin composition that constitutes the resin composition
layer used in the present invention preferably has a fusion peak
temperature only in a temperature range from 120.degree. C. or
higher to 170.degree. C. or lower and also has a heat of fusion
from 5 J/g or more to 20 J/g or less. This resin composition plays
a role in improving the adhesion between a cyclic polyolefin
polymer or a cyclic polyolefin copolymer and a polyolefin layer and
also in improving the flexibility of the multilayered film as a
whole. This resin composition has a fusion peak temperature in a
temperature range from 120.degree. C. or higher to 170.degree. C.
or lower that is derived from the crystalline component of the
resin. If such fusion peak temperature is lower than 120.degree.
C., a multilayered film resistant to sterilization at 121.degree.
C. cannot be constituted. On the other hand, if such fusion peak
temperature exceeds 170.degree. C., the molding temperature is too
high to produce a multilayered film with good appearance. Moreover,
if the heat of fusion is less than 5 J/g, a multilayered film
resistant to sterilization at 121.degree. C. cannot be constituted.
On the other hand, if it exceeds 20 J/g, the adhesion with a cyclic
polyolefin polymer or a cyclic polyolefin copolymer becomes poor,
and delamination (delami) easily occurs after completion of the
sterilization. As a result, there is a fear that the appearance
becomes deteriorated or desired preservability cannot be
obtained.
[0036] Furthermore, when the resin composition has a fusion peak
temperature in a temperature range of lower than 120.degree. C.,
since a component having such fusion peak is melted during
sterilization, the heat resistance of the resin composition is
lost, and as a result, deformation, whitening and the like occur on
the multilayered film. Examples of a resin having a fusion peak
temperature in a temperature range of lower than 120.degree. C.
include high pressure method polyethylene or linear low-density
polyethylene having a density of 0.93 or less, and an
ethylene-.alpha.-olefin copolymer having a density of 0.90 or
less.
[0037] The method for producing the resin composition of the
present invention is not particularly limited, as long as the
produced resin composition satisfies the above-described
conditions, namely, as long as it has a fusion peak temperature
only in a temperature range from 120.degree. C. or higher to
170.degree. C. or lower and also has a heat of fusion from 5 J/g or
more to 20 J/g or less. For example, there can be applied a method,
which comprises: first producing a crystalline propylene
homopolymer having a fusion peak temperature in a temperature range
from 120.degree. C. or higher to 170.degree. C. or lower, or a
propylene-ethylene copolymer containing a small amount of ethylene
(approximately 3% by weight or less) by continuous polymerization;
and then producing a copolymer consisting of substantially
amorphous propylene that does not have a fusion peak temperature in
a temperature range from 120.degree. C. or higher to 170.degree. C.
or lower and approximately 10% to 20% by weight of ethylene; so as
to totally obtain a resin composition having a heat of fusion from
5 J/g or more to 20 J/g or less. There can also be applied a
method, which comprises: producing a crystalline propylene
homopolymer having a fusion peak temperature in a temperature range
from 120.degree. C. or higher to 170.degree. C. or lower, or a
propylene-ethylene copolymer of propylene and a small amount of
ethylene (approximately 3% by weight or less), and a copolymer of
propylene and approximately 10% to 20% by weight of ethylene,
separately; and then blending them; so as to totally obtain a resin
composition having a heat of fusion from 5 J/g or more to 20 J/g or
less.
[0038] The above-described method for producing a resin composition
by continuous polymerization is disclosed, for example, in JP
Patent Publication (Kokai) Nos. 2001-172454 A and 2003-292700
A.
[0039] Further, there are produced: a crystalline propylene
homopolymer having a fusion peak temperature in a temperature range
from 120.degree. C. or higher to 170.degree. C. or lower, a
propylene-ethylene copolymer containing a small amount of ethylene
(approximately 3% by weight or less); a crystalline propylene
homopolymer having a fusion peak temperature in a temperature range
from 120.degree. C. or higher to 170.degree. C. or lower, or a
propylene-ethylene copolymer containing a small amount of ethylene
(approximately 3% by weight or less), produced by continuous
polymerization. Thereafter, a copolymer consisting of amorphous or
semi-crystalline propylene that does not have a fusion peak
temperature in a temperature range from 120.degree. C. or higher to
170.degree. C. or lower and approximately 10% to 20% by weight of
ethylene is produced to obtain a propylene polymer composition. A
propylene copolymer having a fusion peak temperature in a
temperature range from 120.degree. C. or higher to 170.degree. C.
or lower, selected from among the thus obtained propylene polymer
compositions, are blended with a styrene elastomer, so as to obtain
a blended product.
[0040] The above-described styrene elastomer indicates a
hydrogenated derivative of a vinyl aromatic hydrocarbon-conjugated
diene block copolymer. It is one or two or more types of
hydrogenated derivatives of such block copolymer represented by the
formula: a(b-a)n, (a-b)n, or a-b-c (wherein (a) represents a
polymer block of monovinyl-substituted aromatic hydrocarbon; (b)
represents a random copolymer block of a monovinyl-substituted
aromatic hydrocarbon and a conjugated diene, or an elastomeric
polymer block of conjugated diene; (c) represents a block of a
monovinyl-substituted aromatic hydrocarbon and a conjugated diene,
which is a taper block in which the monovinyl-substituted aromatic
hydrocarbon is gradually increased; and n represents an integer of
1 to 5).
[0041] Examples of a monovinyl aromatic hydrocarbon constituting
the above-described polymer block (a), (b) or (c) include styrene,
.alpha.-methylstyrene, (o-, m-, p-)methylstyrene,
1,3-dimethylstyrene, vinylnaphthalene, and vinylanthracene. Of
these, styrene or .alpha.-methylstyrene is preferable. As a
conjugated diene monomer used in the above-described polymer block
(b) or (c), butadiene and/or isoprene are preferable. When
butadiene is used as a single conjugated diene monomer to form the
polymer block (b) or (c), for the purpose of increasing
compatibility with a propylene polymer, after a block copolymer has
been hydrogenated so that a double bond has become saturated, there
are preferably adopted polymerization conditions in which a
1,2-microstructure accounts for 50% or more (by weight) of the
microstructure of polybutadiene. The preferred amount of the
1,2-microstructure is from 50% by weight to 90% by weight. The
amount of the polymer block (a) in the hydrogenated block
copolymer, or the total amount of the vinyl aromatic compounds of
the polymer block (a) and the polymer block (c), is generally from
3% to 30% by weight, and preferably from 5% to 20% by weight. When
the amount of the polymer block (a) or the total amount of the
vinyl aromatic compounds of the polymer block (a) and the polymer
block (c) is less than 3% by weight, the mechanical strength of the
obtained composition tends to be deteriorated. On the other hand,
when the amount of the polymer block (a) or the total amount of the
vinyl aromatic compounds of the polymer block (a) and the polymer
block (c) exceeds 30% by weight, the flexibility and transparency
of the composition tend to be deteriorated.
[0042] The weight average molecular weight of a styrene elastomer
(a hydrogenated derivative of a vinyl aromatic
hydrocarbon-conjugated diene block copolymer) is generally 100,000
to 550,000, preferably 150,000 to 500,000, and more preferably
200,000 to 450,000, as a value relative to polystyrene measured by
gel permeation chromatography. If such weight average molecular
weight is less than 100,000, rubber elasticity and mechanical
strength tend to be deteriorated. On the other hand, if it exceeds
550,000, viscosity becomes high, and molding processability tends
to be deteriorated.
[0043] Examples of the above-described styrene elastomer (a
hydrogenated derivative of a vinyl aromatic hydrocarbon-conjugated
diene block copolymer) include commercially available products such
as "KRATON-G" manufactured by Kraton Polymers, "SEPTON" &
"HYBRAR" manufactured by Kuraray Co., Ltd., "Toughtech"
manufactured by Asahi Kasei Corporation, "Dynaron" manufactured by
JSR, and "SIBSTAR" composed of a styrene block and an isobutylene
block obtained by cationic polymerization, manufactured by Kaneka
Corporation.
[0044] As a resin composition having a fusion peak temperature in a
temperature range from 120.degree. C. or higher to 170.degree. C.
or lower and also having a heat of fusion from 5 J/g or more to 20
J/g or less as obtained above, ZELAS MC729 manufactured by
Mitsubishi Chemical Corporation is preferable.
[0045] The thickness of this resin composition layer is not
particularly limited. It is preferably from 20 .mu.m or more to 120
.mu.m or less, and more preferably from 20 .mu.m or more to 75
.mu.m or less. Moreover, when resin composition layers are disposed
on both sides of a cyclic polyolefin layer, the thickness of a
resin composition layer on the seal layer side may be identical to
or different from the thickness of a resin composition layer on the
outermost layer side.
[0046] Examples of the cyclic polyolefin polymer or cyclic
polyolefin copolymer constituting the cyclic polyolefin layer used
in the present invention include: a copolymer of ethylene and
dicyclopentadiene; a copolymer of ethylene and a norbornene
compound; a ring-opening polymer of a cyclopentadiene derivative; a
ring-opening copolymer of various cyclopentadiene derivatives; and
a hydrogenation product thereof. Of these, a hydrogenation product
of a copolymer of ethylene and a norbornene compound, or a
hydrogenation product of a ring-opening (co)polymer of one or more
types of cyclopentadiene derivatives is preferably used. A
ring-opening polymer hydrogenation product of dicyclopentadiene or
a derivative thereof is more preferable.
[0047] The above-described resin includes: a polymer having a
repeating unit represented by the formula (1) as shown below and a
repeating unit represented by the formula (1') as shown below; and
a polymer having a repeating unit represented by the formula (2) as
shown below.
##STR00003##
(wherein, in formulae (1) and (1'), each of Ra, Ra', Rb and Rb'
identically or differently represents a hydrogen, a hydrocarbon
residue, or a polar group such as a halogen, an ester, a nitrile or
a pyridyl; Ra, Ra', Rb and Rb' may bind to one another to form a
ring; each of m and m' represents an integer of 1 or greater; and
each of n and n' represents an integer of 0 or 1 or greater).
##STR00004##
(wherein, in formula (2), each of Rc and Rd identically or
differently represents a hydrogen, a hydrocarbon residue, or a
polar group such as a halogen, an ester, a nitrile or a pyridyl;
R.sup.3 and R.sup.4 may bind to each other to form a ring; each of
x and z represents an integer of 1 or greater; and y represents an
integer of 0 or 1 or greater).
[0048] The polymer having the repeating units represented by the
formulae (1) and (1') is produced by polymerizing one or two or
more types of monomers according to a known ring-opening
polymerization method, or further by hydrogenating the thus
obtained ring-opening polymer according to an ordinary method.
Specific examples of such polymer include "ZEONOA (product name;
registered trademark)" as a hydrogenated polymer manufactured by
Zeon Corporation, and "ARTON (product name; registered trademark)"
manufactured by Japan Synthetic Rubber Co., Ltd. The polymer having
the structural unit represented by the formula (2) is produced by
subjecting one or two or more types of norbornene monomers used as
monomers and ethylene to addition copolymerization according to a
known method, or further by hydrogenating the obtained product
according to an ordinary method. Specific examples of such polymer
include "APEL (product name; registered trademark)" manufactured by
Mitsui Chemicals, Inc., and "TOPAS (product name; registered
trademark)" manufactured by Polyplastics Co., Ltd.
[0049] Preferred examples of the cyclic polyolefin polymer or
cyclic polyolefin copolymer used in the present invention include
"ZEONOA (registered trademark)" and "TOPAS (registered
trademark)."
[0050] Among the above-exemplified resins containing the
above-described polymers having the structural units represented by
the formulae (1) and (1') and the formula (2), the hydrogenation
products thereof are all saturated polymers. Thus, the
hydrogenation products are excellent in terms of heat resistance,
transparency and stability, as well as a gas-shielding property and
a moisture-shielding property. The cyclic polyolefin polymer used
in the present invention has a glass transition temperature
(T.sub.g) of preferably 70.degree. C. or higher, and more
preferably 80.degree. C. to 120.degree. C. Moreover, the range of
the molecular weight of the present cyclic polyolefin polymer is
preferably 10,000 to 100,000, and more preferably 20,000 to 50,000,
relative to a number average molecular weight <Mn> measured
by gel permeation chromatography (GPC) using cyclohexane as a
solvent. Furthermore, from another viewpoint, the melt flow rate
(230.degree. C., 21.2 N) value of the present cyclic polyolefin
polymer is preferably 1 to 20 (g/10 minutes). When an unsaturated
bond remaining in the molecular chain of cyclic polyolefin is
saturated by hydrogenation, the hydrogenation rate is preferably
90% or more, more preferably 95% or more, and particularly
preferably 99% or more.
[0051] The cyclic polyolefin polymer or the cyclic polyolefin
copolymer may be used in the state of a single layer, or may also
be used as a mixed resin formed by mixing it with another resin.
When the cyclic polyolefin polymer or the cyclic polyolefin
copolymer is used as a mixed resin, if the content of the cyclic
polyolefin polymer or cyclic polyolefin copolymer in the mixed
resin is less than 60% by weight, the effect of preventing the
adsorption of an agent is decreased. On the other hand, if the
content of the cyclic polyolefin in the mixed resin exceeds 95% by
weight, the flexibility of a multilayered film as a whole is
decreased. Accordingly, when the cyclic polyolefin polymer or
cyclic polyolefin copolymer is used in the form of a mixed resin,
the content of the cyclic polyolefin polymer or cyclic polyolefin
copolymer is desirably from 60% by weight or more to 95% by weight
or less.
[0052] Examples of a resin to be mixed with the cyclic polyolefin
polymer or cyclic polyolefin copolymer include polyethylene,
polypropylene, poly 1-butene, poly 4-methyl-1-pentene, an
ethylene-propylene copolymer, a mixture of polypropylene and
polyethylene or polybutene, a partially cross-linked product of the
aforementioned polyolefin, an ethylene-vinyl acetate copolymer, an
ethylene-(meth)acrylic acid ester copolymer, an
ethylene-(meth)acrylic acid copolymer, and an ethylene-maleic
anhydride copolymer. Of these, preferred examples of such resin
include an ethylene homopolymer (product name: HARMOREC (registered
trademark)), an .alpha.-olefin copolymer (product name: TOUGHMER
(registered trademark)), and an ethylene-1-octene copolymer
(product name: MORETEC (registered trademark)).
[0053] The thickness of the cyclic polyolefin layer is determined
within the aforementioned range, while taking into consideration
the balance between the effect of preventing the adsorption of an
agent and the flexibility of a multilayered film as a whole. If the
thickness of the cyclic polyolefin layer is less than 10 .mu.m, the
effect of preventing the adsorption of an agent is decreased. On
the other hand, if the thickness exceeds 80 .mu.m, the flexibility
of a multilayered film as a whole is decreased. The particularly
preferred range of the thickness of the cyclic polyolefin layer can
be from 10 .mu.m to 50 .mu.m. More preferably, the thickness of the
cyclic polyolefin layer can be from 10 .mu.m to 30 .mu.m.
[0054] As polypropylene constituting the seal layer used in the
present invention, there can be used not only a propylene
homopolymer, but also a copolymer produced by copolymerizing
propylene with a small amount (preferably 10% by weight or less) of
.alpha.-olefin such as ethylene or 1-butene, a copolymer produced
by multistage polymerization of propylene with .alpha.-olefin and
the like as disclosed, for example, in JP Patent Publication
(Kokai) No. 2001-226435 A. Among others, in order to alleviate the
rigidness of the cyclic polyolefin layer and to improve the
flexibility of the multilayered film, polypropylene of a relatively
flexible grade, having a bending elasticity of 400 to 600 MPa,
which has been commonly used as a medical container, is preferably
used. Moreover, from another viewpoint, polypropylene having a melt
flow rate (230.degree. C., 21.2 N) value of 1 to 4 (g/10 minutes)
is preferably used. A specific example of the polypropylene that
can be used in the present invention is ZELAS (registered
trademark) manufactured by Mitsubishi Chemical Corporation. In
particular, ZELAS MC607 having a fusion peak temperature in a
temperature range from 125.degree. C. to 135.degree. C. is
preferably used. The thickness of the seal layer is not
particularly limited. It is preferably from 20 to 120 .mu.m.
[0055] A layer comprising polypropylene constituting the outermost
layer used in the present invention may be constituted, not only
with a propylene homopolymer, but also with a copolymer produced by
copolymerizing propylene with a small amount (preferably 10% by
weight or less) of .alpha.-olefin such as ethylene or 1-butene, a
copolymer produced by multistage polymerization of propylene with
.alpha.-olefin as disclosed, for example, in JP Patent Publication
(Kokai) No. 2001-226435 and the like. Moreover, a compound of such
homopolymer or copolymer with another polyolefin or resin may also
be used. Among others, in order to alleviate the rigidness of the
cyclic polyolefin layer and to improve the flexibility of a
multilayered film, polypropylene of a relatively flexible grade,
having a bending elasticity of 400 to 600 MPa, which has been
commonly used as a medical container, is preferably used.
Furthermore, from another viewpoint, the melt flow rate
(230.degree. C., 21.2 N) value of the outermost layer is preferably
set at 1 to 4 (g/10 minutes). A specific example of the
polypropylene constituting the outermost layer that can be
preferably used in the present invention is ZELAS (registered
trademark) manufactured by Mitsubishi Chemical Corporation. In
particular, ZELAS MC715 having a fusion peak temperature in a
temperature range from 160.degree. C. to 170.degree. C. is
preferably used. The thickness of the outermost layer is not
particularly limited. It is preferably from 20 to 100 .mu.m.
[0056] Hence, a layer containing polypropylene having a high fusion
peak temperature is disposed as an outermost layer, and a
polypropylene layer having a relatively low fusion peak temperature
is disposed as a seal layer, so that the heat-sealing properties of
a multilayered film containing a cyclic polyolefin layer are
significantly improved, thereby producing a practical
container.
[0057] Further, from the viewpoint of shock resistance, handling
ability during the filling of the container with a medicament, and
the moldability of the container, the plastic container and
multilayered film of the present invention obtained with the
above-described structure desirably has a tensile elasticity of 300
MPa or less.
[0058] The active ingredient of a liquid-state medicament that can
be filled into the plastic container provided by the present
invention is not limited. Preferred examples of such active
ingredient include the pyrazolone derivative represented by the
formula (I) defined in the present specification, a physiologically
acceptable salt thereof, a hydrate thereof, and a solvate
thereof.
[0059] The compound represented by the formula (I) may also have a
structure represented by general formula (I') or (I'') as shown
below, as a result of tautomerism. As a matter of convenience, a
tautomer is shown by the formula (I) in the present specification.
However, the presence of the following tautomers is obvious to
persons skilled in the art.
##STR00005##
[0060] In the formula (I), the aryl group represented by R.sup.1
may be either a monocyclic or polycyclic aryl group. Examples of
such aryl group include: phenyl groups; naphthyl groups; alkyl
groups such as a methyl group and a butyl group; alkoxy groups such
as a methoxy group and a butoxy group; halogen atoms such as a
chlorine atom; and phenyl groups substituted with substituents such
as a hydroxyl group. The same applies to aryl portions in other
substituents (an aryloxy group, etc.) having such aryl
portions.
[0061] The alkyl group containing 1 to 5 carbon atoms represented
by each of R.sup.1, R.sup.2 and R.sup.3 may be either a linear or
branched alkyl group. Examples of such alkyl group include a methyl
group, an ethyl group, a propyl group, an isopropyl group, a butyl
group, an isobutyl group, a sec-butyl group, a tert-butyl group,
and a pentyl group. The same applies to an alkyl portion in another
substituent (an alkoxycarbonylalkyl group) having such alkyl
portion.
[0062] Examples of the alkoxycarbonylalkyl group containing 3 to 6
carbon atoms in total represented by R.sup.1 include a
methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a
propoxycarbonylmethyl group, a methoxycarbonylethyl group, and a
methoxycarbonylpropyl group.
[0063] Examples of the alkylene group containing 3 to 5 carbon
atoms represented by each of R.sup.1 and R.sup.2 include a
trimethylene group, a tetramethylene group, a pentamethylene group,
a methyltrimethylene group, an ethyltrimethylene group, a
dimethyltrimethylene group, and a methyltetramethylene group.
[0064] Examples of the aryloxy group represented by R.sup.2 include
a p-methylphenoxy group, a p-methoxyphenoxy group, a
p-chlorophenoxy group, and a p-hydroxyphenoxy group. Examples of
the arylmercapto group include a phenylmercapto group, a
p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a
p-chlorophenylmercapto group, and a p-hydroxyphenylmercapto
group.
[0065] Examples of the hydroxyalkyl group containing 1 to 3 carbon
atoms represented by each of R.sup.2 and R.sup.3 include a
hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl
group. Examples of the cycloalkyl group containing 5 to 7 carbon
atoms represented by R.sup.3 include a cyclopentyl group, a
cyclohexyl group, and a cycloheptyl group.
[0066] Examples of the alkoxy group containing 1 to 5 carbon atoms
as a substituent of the phenyl group represented by R.sup.3 include
a methoxy group, an ethoxy group, a propoxy group, an isopropoxy
group, a butoxy group, and a pentyloxy group. Examples of the
alkoxycarbonyl group containing 2 to 5 carbon atoms in total
include a methoxycarbonyl group, an ethoxycarbonyl group, a
propoxycarbonyl group, and a butoxycarbonyl group. Examples of the
alkylmercapto group containing 1 to 3 carbon atoms include a
methylmercapto group, an ethylmercapto group, and a propylmercapto
group. Examples of the alkylamino group containing 1 to 4 carbon
atoms include a methylamino group, an ethylamino group, a
propylamino group, and a butylamino group. Examples of the
dialkylamino group containing 2 to 8 carbon atoms in total include
a dimethylamino group, a diethylamino group, a dipropylamino group,
and a dibutylamino group.
[0067] A preferably used compound (I) is
3-methyl-1-phenyl-2-pyrazolin-5-one.
[0068] The compounds represented by the formula (I) are all known
compounds. These compounds can be easily synthesized by persons
skilled in the art according to the method described in JP Patent
Publication (Kokoku) No. 5-31523 B (1993), and the like.
[0069] When the plastic container provided by the present invention
is filled with a solution comprising, as an active ingredient, the
pyrazolone derivative represented by the above-described formula
(I), a physiologically acceptable salt thereof, a hydrate thereof,
or a solvent thereof (hereinafter generically referred to as a
"pyrazolone derivative," at times), for example, when an infusion
bag is prepared by filling the plastic container with such agent,
the pyrazolone derivative is dissolved in a solvent (for example,
an infusion solution, etc.), to a concentration from approximately
0.06 mg/mL or higher to approximately 2 mg/mL or lower, preferably
from approximately 0.1 mg/mL or higher to approximately 0.6 mg/mL
or lower, and more preferably approximately 0.3 mg/mL. Thereafter,
a pH adjuster is added to the solution, as desired, so as to adjust
the pH of the solution. Thereafter, other additives are further
added thereto, as desired, so as to prepare an agent filled in the
infusion bag.
[0070] In order to prepare a liquid-state medicament to be placed
in the plastic container of the present invention, all types of
ingredients may be used, in addition to the active ingredient, as
long as they are commonly used as medicaments. For example, one or
two or more types of ingredients arbitrarily selected from among
electrolytes, sugars, vitamins, protein amino acids, etc., which
are dissolved in any given concentrations in water (for example,
distilled water for injection, etc.) may be used. An example of
such electrolyte is sodium chloride. These arbitrary ingredients
may be used in any given concentration, singly or in combination of
two or more types. A preferred example is sodium chloride or the
like that has been dissolved in any given concentration in water
(for example, distilled water for injection, etc.). In the case of
sodium chloride, the content of this ingredient is preferably
equivalent to that of a normal saline, namely, approximately 0.9%
(W/V). Other than this ingredient, a pH adjuster that is commonly
used as a pH adjuster for injection may be used without particular
limitations.
[0071] The types of other additives that can be used to prepare the
liquid-state medicament are not particularly limited, as long as
they are commonly used as additives for injections. In the present
invention, other preferred additives include pharmaceutical
additives described in "Iyakuhin Tenkabutsu Jiten (Pharmaceutical
Additive Dictionary)," Yakuji Nippo 2000 (edited by the Japan
Pharmaceutical Excipients Council), and the like. In general, these
additives are mixed at ratios commonly applied to injections. In
addition, these additives may be separated, for example, into a
stabilizer, a surfactant, a buffer, a solubilizing agent, an
antioxidant, an antifoaming agent, an isotonizing agent, an
emulsifier, a suspending agent, a preservative, a soothing agent, a
resolvent, a solubilization aid, and the like, and may be then
used. These additive may be used in combination of two or more
ingredients, as desired.
[0072] The form of the plastic container of the present invention
is not particularly limited, as long as it is hermetically sealable
and is able to maintain the sterility of the content. In general,
containers such as an infusion bag, a syringe, an ampule and a
vial, which are used to contain an injection solution, are
preferable. Of these, an infusion bag is particularly preferable.
Moreover, in order to confirm the presence or absence of the
generation of insoluble foreign matters, these containers are
preferably transparent and colorless. However, an opaque, colored
container may also be used.
[0073] When a liquid-state medicament is placed in the plastic
container provided by the present invention, the plastic container
can be produced by filling it with the liquid-state medicament and
then hermetically sealing it. Moreover, a sterilization operation
is carried out on the plastic container in any given process, so as
to produce a plastic container maintaining sterility. Furthermore,
before filling the container with the medicament, the agent
solution may be filtrated with a dust-proof filter (for example, a
0.45-.mu.m methylcellulose membrane, a 0.45-.mu.m nylon 66
membrane, a 0.45-.mu.m polyvinylidene fluoride membrane, etc.), as
desired. Specific methods for sterilizing the plastic container of
the present invention include a hot water immersion sterilization
method, a hot water shower sterilization method, and a
high-pressure steam sterilization (autoclave) method. Such hot
water immersion sterilization method, hot water shower
sterilization method, and high-pressure steam sterilization method
are carried out, for example, after the agent solution has been
prepared and has been then filled into the plastic container of the
present invention. The high-pressure steam sterilization is
preferably carried out, for example, under conditions of a
temperature of 100.degree. C. to 125.degree. C. for 5 to 40
minutes. The plastic container of the present invention is
sterilized, preferably at 115.degree. C. for 30 minutes or longer,
and more preferably 121.degree. C. for 15 minutes or longer.
[0074] The plastic container and multilayered film provided by the
present invention is desirably composed of five or more layers.
Specifically, an outermost layer-a resin composition layer-a cyclic
polyolefin layer-a resin composition layer-a seal layer is
desirably used as a base. By adopting such structure, it becomes
possible to sterilize the plastic container of the present
invention at 121.degree. C. for 15 minutes or longer, and as, a
result, a plastic container that has flexibility and high shock
resistance and can be easily filled with an agent solution can be
produced. Moreover, it is also possible to add any given resin
layers between any given layers of the outermost layer-resin
composition layer-cyclic polyolefin layer-resin composition
layer-seal layer. The any given resin layers added herein include
polyolefins such as polypropylene, polyamides, polyesters such as
polyethylene terephthalate or polybutylene terephthalate, and
ethylene-vinyl alcohol copolymers. Specifically, polyolefins
prepared by grafting these polar materials with .alpha.,.beta.
unsaturated carboxylic acids having adhesiveness therewith,
copolymers of carboxylic acids and ethylenes, etc. may be used. Of
these, preferred examples of the resin layer include the resin
composition layer as described above in the present specification,
a polypropylene layer, and a layer containing polypropylene. In
order to determine the structure of layers, it is desired to adjust
the layer structure, such that the tensile elasticity of the
obtained multilayered film can be 300 MPa or less.
[0075] When the form of the plastic container provided by the
present invention is an infusion bag, it can be produced by sealing
the peripheral portions of the multilayered films provided by the
present invention according to an ordinary method and molding it
into the form of a bag. The thickness of the multilayered film is
preferably 500 .mu.m or less, and particularly preferably 200 to
300 .mu.m.
[0076] The multilayered film provided by the present invention can
be produced by applying various types of conventionally known
methods such as a co-extrusion inflation method or a co-extrusion
T-die method.
[0077] The plastic container of the present invention may be
wrapped with a light-shielding material to suppress the
permeability of a light with a specific wavelength. The type of a
wrapping material used in such wrapping is not particularly
limited, as long as it is a commonly used light-shielding wrapping
material. Specifically, a bag made of a material for suppressing
the permeability of a light with a specific wavelength, a bag made
of a light-shielding material such as plastic or aluminum, a shrink
wrapping material (for example, a shrink label, etc.) using
light-shielding plastic, a blister wrapping material, and the like
may be used. By the combined use of these light-shielding
materials, their light-shielding properties can be further
enhanced.
[0078] Furthermore, the plastic container of the present invention
may be placed in a poorly air-permeable container. The type of such
poorly air-permeable container is not particularly limited, as long
as it is produced from a commonly used, poorly air-permeable
material. Specifically, it is adequate if such container hardly
gives passage to oxygen or nitrogen. Examples of such poorly
air-permeable container include an aluminum container and a PET
film container formed by silica evaporation. Furthermore, an oxygen
absorber may also be placed in such poorly air-permeable
container.
EXAMPLES
[0079] The present invention will be more specifically described in
the following production example, test example, and examples.
However, these examples are not intended to limit the scope of the
present invention.
Production Example of Infusion Bag
[0080] Films having the structures shown in Table 1 were produced
using a water-cooled type inflation device capable of molding 6
types of 6-layered films. Thereafter, a polyethylene or
polypropylene port was deposited on each film, so as to mold a
100-mL infusion bag on which a polyethylene or polypropylene port
was deposited. That is to say, the peripheral portions of the
multilayered films shown in Table 1 were heat-sealed in a state in
which the seal layers were laminated on each other such that they
faced each other, so as to produce each infusion bag. In Table 1,
films A01, A03, C01 and C02 are the examples of the present
invention, and films A02, A04, A05, B01, B02 and B03 are the
reference examples of the present invention.
TABLE-US-00001 TABLE 1 Film composition Outer layer 1 2 3 4
(Barrier layer) 5 6 inner layer A01 ZELAS MC715 ZELAS MC717 TOPAS
9506F-04 ZELAS MC717 ZELAS MC607 30 .mu.m 70 .mu.m 10 .mu.m 60
.mu.m 60 .mu.m A02 ZELAS MC715 ZELAS MC717 TOPAS 9506F-04 ZELAS
MC717 MORETEC 30 .mu.m 70 .mu.m 10 .mu.m 60 .mu.m 0248Z 60 .mu.m
A03 ZELAS MC715 ZELAS MC717 TOPAS 9506F-04/ ZELAS MC717 ZELAS MC607
30 .mu.m 70 .mu.m MORETEC 0168N 60 .mu.m 50 .mu.m 20 .mu.m A04
MORETEC 0168N HARMOREC NV325N/ TOPAS 9506F-04 ZELAS MC717 ZELAS
MC607 30 .mu.m TOUGHMER 04085 /MORETEC 0168N 60 .mu.m 50 .mu.m 70
.mu.m 20 .mu.m A05 MORETEC 0168N HARMOREC NV325N/ ZEONOA 1060R
ZELAS MC717 ZELAS MC607 30 .mu.m TOUGHMER 04085 10 .mu.m 60 .mu.m
60 .mu.m 70 .mu.m B01 ZELAS MC715 TOPAS 8007 ZELAS MC607 70 .mu.m
20 .mu.m 110 .mu.m B02 ZELAS MC715 ZEONOA 1060R ZELAS MC607 70
.mu.m 20 .mu.m 110 .mu.m B03 ZELAS MC715 ZEONOA 1060R ZELAS MC607
70 .mu.m 30 .mu.m 100 .mu.m C01 ZELAS MC715 ZELAS MC717 ZELAS MC729
ZEONOA 1060R ZELAS MC729 ZELAS MC607 20 .mu.m 20 .mu.m 30 .mu.m 15
.mu.m 75 .mu.m 40 .mu.m C02 ZELAS MC715 ZELAS MC717 ZELAS MC729
ZEONOA 1060R ZELAS MC729 ZELAS MC607 20 .mu.m 35 .mu.m 45 .mu.m 15
.mu.m 75 .mu.m 40 .mu.m 2 3 Comparative ZELAS RT-267A-1 ZELAS MC717
ZELAS 7023 Example 1 40 .mu.m 120 .mu.m 40 .mu.m
[0081] In the table, ZELAS (registered trademark) is an olefin
(homopolypropylene) thermoplastic elastomer distributed by
Mitsubishi Chemical Corporation. ZELAS MC717 and ZELAS MC729 are
resin compositions comprising blended products of propylene
polymers and styrene elastomers. TOPAS (registered trademark) is a
cyclic polyolefin copolymer distributed by Polyplastics Co., Ltd.
MORETEC (registered trademark) is a linear low-density polyethylene
C8 copolymer produced by copolymerizing ethylene and 1-octene,
which is distributed by Prime Polymer Co., Ltd. HARMOREC
(registered trademark) is polyethylene distributed by Japan
Polyethylene Corporation. TOUGHMER (registered trademark) is an
.alpha.-olefin copolymer distributed by Mitsui Chemicals, Inc.
ZEONOA (registered trademark) is a cyclic polyolefin polymer
distributed by Zeon Corporation.
Example 1
[0082] A solution obtained by diluting commercially available
Radicut (registered trademark) injection 30 mg (manufactured and
distributed by Mitsubishi Tanabe Pharma Corporation) with 100 mL of
a normal saline was filled into an infusion bag formed with each of
various types of films A01 to A05 and Comparative Example 1 shown
in Table 1, and it was then sterilized (115.degree. C., 30
minutes). The content of a main component (Edaravone) was measured
before and after the sterilization. The results are shown in Table
2. In the case of using a film comprising a cyclic polyolefin
polymer or a cyclic polyolefin copolymer as a barrier layer, a
significant reduction in the content of the component was not
observed after the sterilization. On the other hand, in the case of
using a film constituted only with polypropylene (ZELAS (registered
trademark) RT-267A-1, MC717, 7023), a reduction in the content of
the component was observed after sterilization.
TABLE-US-00002 TABLE 2 Medicament adsorption on bag during
sterilization in case of using COP or COC as barrier layer After
Reduction rate After filling sterilization in content Film A01
101.1 99.1 2.0 Film A03 101.1 98.3 2.8 Comparative 102.7 98.4 4.3
Example 1
Test Example 1
[0083] A solution obtained by diluting commercially available
Radicut (registered trademark) injection 30 mg (manufactured and
distributed by Mitsubishi Tanabe Pharma Corporation) with 100 mL of
a normal saline was filled into an infusion bag formed with each of
various types of films A05 and B01 to B03 shown in Table 1, and it
was then sterilized (115.degree. C., 30 minutes). The content of a
main component (Edaravone) was measured before and after the
sterilization. The results are shown in Table 3. Films comprising a
cyclic polyolefin polymer or a cyclic polyolefin copolymer as a
barrier layer were able to suppress the adsorption of the component
during the sterilization at almost same levels. If the thickness of
such cyclic polyolefin polymer was 10 .mu.m or more, it
sufficiently exhibited its functions.
TABLE-US-00003 TABLE 3 After filling After sterilization Reduction
rate in content Difference in medicament adsorption on bag in case
of using COP or COC as barrier layer Film B01 103.1 100.2 2.9 Film
B02 103.1 101.7 1.4 Influence of thickness of COP on medicament
adsorption Film A05 97.9 96.1 1.8 Film B02 97.9 97.7 0.2 Film B03
97.9 97.3 0.6
Example 2
[0084] A solution obtained by diluting commercially available
Radicut (registered trademark) injection 30 mg (manufactured and
distributed by Mitsubishi Tanabe Pharma Corporation) with 100 mL of
a normal saline was filled into an infusion bag formed with each of
various types of films of C01, C02 and Comparative Example 1 shown
in Table 1, and it was then sterilized (115.degree. C., 30
minutes). Thereafter, a severe test (60.degree. C., 4 weeks) was
carried out on each sample wrapped with a second wrapping material
containing AGELESS as an oxygen absorber and having a suppressed
gas permeability, which had been formed by silica evaporation. As
shown in Table 4, in the case of the bag of Comparative Example 1,
a reduction in the content of the component was observed over time.
However, such reduction in the content of the component was not
observed in the case of the bags of C01 and C02.
TABLE-US-00004 TABLE 4 Severe stability test of bags containing COP
as barrier layers (60.degree. C.) After After filling sterilization
Week 1 Week 2 Week 4 Film C01 97.9 96.4 96.2 97.3 98.2 Film C02
97.9 96.1 96.7 96.9 97.5 Comparative 102.7 98.4 91.0 90.9 Example
1
[0085] In the table, in the case of films C01 and C02, the content
of Edaravone after 4 weeks have passed is higher than the content
of Edaravone after completion of the sterilization. This is because
the solvent (water) in the bag was evaporated to outside of the bag
during the storage at 60.degree. C.
INDUSTRIAL APPLICABILITY
[0086] According to the present invention, a plastic container
suitable for containing a liquid-state medicament and a
multilayered film used to produce this container can be provided.
The plastic container and the multilayered film obtained by the
present invention are able to suppress a reduction in the content
of the active ingredient of a medicament contained therein, do not
cause delamination due to high-pressure steam sterilization and
long-term conservation, and are excellent in terms of shock
resistance, handling ability during the filling of the container
with a medicament, and the moldability and transparency of the
container.
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