U.S. patent application number 12/934361 was filed with the patent office on 2011-05-05 for composition for stabilizing beta-blocker and transdermally absorbable preparation comprising the same.
Invention is credited to Miho Ishigure, Takeshi Ito.
Application Number | 20110104247 12/934361 |
Document ID | / |
Family ID | 41113863 |
Filed Date | 2011-05-05 |
United States Patent
Application |
20110104247 |
Kind Code |
A1 |
Ito; Takeshi ; et
al. |
May 5, 2011 |
COMPOSITION FOR STABILIZING BETA-BLOCKER AND TRANSDERMALLY
ABSORBABLE PREPARATION COMPRISING THE SAME
Abstract
The present invention relates to a transdermally absorbable
composition which is capable of retaining a .beta.-blocker stably
for a long period. More specifically, the present invention relates
to a transdermally absorbable composition for stabilizing a
.beta.-blocker, which comprises a polymer compound having an amino
group, a polyvalent carboxylic acid ester, a fatty acid ester and
an acrylic polymer compound.
Inventors: |
Ito; Takeshi; (Fukuoka-ken,
JP) ; Ishigure; Miho; (Kagawa-Ken, JP) |
Family ID: |
41113863 |
Appl. No.: |
12/934361 |
Filed: |
March 25, 2009 |
PCT Filed: |
March 25, 2009 |
PCT NO: |
PCT/JP2009/055964 |
371 Date: |
January 21, 2011 |
Current U.S.
Class: |
424/449 ;
424/78.02 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
9/10 20180101; A61P 9/12 20180101; A61P 29/00 20180101; A61K 31/138
20130101; A61P 9/06 20180101; A61P 43/00 20180101; A61K 9/7061
20130101; A61K 9/7084 20130101 |
Class at
Publication: |
424/449 ;
424/78.02 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/78 20060101 A61K031/78; A61P 9/10 20060101
A61P009/10 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 25, 2008 |
JP |
2008-077903 |
Claims
1-22. (canceled)
23. A composition for stabilizing a .beta.-blocker, which comprises
the .beta.-blocker, a polymeric compound comprising an amino group,
a polyvalent carboxylic acid ester, a fatty acid ester and an
acrylic polymer compound, wherein said .beta.-blocker is
bisoprolol, betaxolol or a salt thereof, said polymeric compound
comprising an amino group is a C1-6 alkyl(meth)acrylate-C1-6
alkyl(meth)acrylate-di-C1-6 alkylamino C1-6 alkyl(meth)acrylate
copolymer, said polyvalent carboxylic acid ester is a citric acid
di-C1-3 alkyl ester or sebacic acid tri-C1-3 alkyl ester, said
fatty acid ester is a C4-18 fatty acid C1-6 alkyl ester, and said
acrylic polymer compound is a C1-10 alkyl(meth)acrylate-hydroxy
C1-6 alkyl(meth)acrylate-C1-6 alkylepoxide(meth)acrylate-vinyl C1-6
carboxylate copolymer.
24. A composition according to claim 23 for the transdermally
absorbable preparation.
25. A composition according to claim 23, wherein the content of
said .beta.-blocker is in the range of 10% by mass or more.
26. A composition according to claim 23, wherein the content of
said .beta.-blocker is in the range of 15-30% by mass or more.
27. A composition according to claim 23, wherein said polymeric
compound comprising an amino group is a C1-3
alkyl(meth)acrylate-C1-3 alkyl(meth)acrylate-di-C1-3 alkylamino
C1-3 alkyl(meth)acrylate copolymer.
28. A composition according to claim 23, wherein said fatty acid
ester is a C12-16 fatty acid C1-3 alkyl ester.
29. A composition according to claim 23, wherein said an acrylic
polymer compound is a C5-8 alkyl(meth)acrylate-hydroxy C1-3 alkyl
(meth)acrylate-C1-3 alkyl epoxide(meth)acrylate-vinyl C1-3
carboxylate copolymer.
30. A composition according to claim 23, further comprising a
higher alcohol.
31. A composition according to claim 30, wherein said higher
alcohol a C6-20 alcohol.
32. A composition according to claim 30, wherein said higher
alcohol is an oleyl alcohol.
33. A composition according to claim 23, wherein said
.beta.-blocker is bisoprolol, betaxolol or a salt thereof, said
polymeric compound comprising an amino group is a
methyl(meth)acrylate-butyl(meth)acrylate-dimethylaminoethyl(meth)acrylate
copolymer, said polyvalent carboxylic acid ester is diethyl
citrate, said fatty acid ester is isopropyl myristate, and said
acrylic polymer compound is a 2-ethylhexyl acrylate-hydroxyethyl
acrylate-glycidyl(meth)acrylate-vinyl acetate copolymer.
34. A transdermally absorbable preparation comprising, a laminate
comprising, in the order from the side-contacting side, an outer
membrane and a drug containing layer, a fixing means for fixing
said laminate on the skin, wherein said drug containing layer
comprises a composition according to claim 23 and wherein said
outer membrane is a drug permeable polymer membrane which ensures
controlled release of the .beta.-blocker into the skin and is
provided on the skin-contacting surface of the laminate.
35. A transdermally absorbable preparation according to claim 34,
wherein said outer membrane is a microporous membrane having
.beta.-blocker permeable pores.
36. A transdermally absorbable preparation according to claim 34,
wherein said outer membrane comprises a polypropylene or
ethylene-vinyl acetate copolymer.
Description
REFERENCE OF RELATED APPLICATIONS
[0001] The present application claims the benefit of priority from
Japanese Patent Application No. 2008-077903 filed on Mar. 25, 2008,
the entire disclosure of which is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a composition for
stabilizing .beta.-blocker and a transdermally absorbable
preparation comprising the composition.
BACKGROUND OF THE INVENTION
[0003] .beta.-blocker is a drug for blocking the .beta.-blocker
receptor of sympathetic nerve relating to the exitation of heart
and vasoconstriction and mainly used for the treatment or
prevention of diseases including essential hypertension, angina
pectoris and arrhythmia. Pharmaceutical preparations containing the
.beta.-blocker are commercially available primarily in the form of
tablets and include, for example, Maintate.TM. (Mitsubishi Tanabe
Pharma Corporation, containing bisoprolol fumarate) and Kerlong.TM.
(Mitsubishi Tanabe Pharma Corporation, containing betaxolol
hydrochloride).
[0004] It is important for the therapy and prophylaxis of diseases
such as essential hypertension, angina pectoris and arrhythmia to
maintain the blood concentration of .beta.-blocker for a long
period and to control blood pressure and heart rate. Thus, the
development of a transdermally absorbable preparation of a
.beta.-blocker has recently attracted a considerable attention in
order to administer the .beta.-blocker to a living body for a long
period and to control its blood concentration. However, the
.beta.-blocker unfortunately tends to be generally decomposed, and
thus it often becomes difficult to maintain the .beta.-blocker
within the transdermally absorbable preparation for a long period
including its shelf life. For instance, it has been described in
Japanese Patent Laid-Open Publication No. 2002-308762 that
bisoprolol as a .beta.-blocker tends to be hydrolyzed in
preparations.
[0005] It has also been described in WO2005/072716 that relative
humidity is controlled by enclosing a drying agent in a packaging
bag in order to improve the storage stability of a transdermally
absorbable preparation containing bisoprolol. However, no technique
has been described with regard to the improvement of the storage
stability of a transdermally absorbable preparation containing a
.beta.-blocker.
[0006] A transdermally absorbable preparation comprising an
adhesive layer containing bisoprolol and polyisobutylene has also
been described in WO2007/029781. It has been described that the
storage stability of bisoprolol is improved by adding
polyisobutylene to the adhesive layer in this transdermally
absorbable preparation. However, it seems that .beta.-blocker such
as bisoprolol is less soluble in polyisobutylene, which is thus
hard to contain a high concentration of a drug required for the
administration for a long period. For instance, in the case of
transdermal administration for a long period including 3 days to 1
week, the drug in the transdermally absorbable preparation may be
exhausted.
[0007] Therefore, it can be said that a composition useful for a
transdermally absorbable preparation which comprises a
.beta.-blocker in a high dosage suitable for administration for a
long period and can be stably retained for a long period is still
required.
SUMMARY OF THE INVENTION
[0008] The present inventors have now found that a composition
comprising certain components can contain a .beta.-blocker in a
high dosage suitable for a long term administration with a
transdermally absorbable preparation and can retain the
.beta.-blocker stably for a long period. The present invention is
based on the findings.
[0009] Thus, the object of the present invention is to provide a
composition which can comprises a .beta.-blocker in a high dosage
suitable for a long term transdermal administration and can retain
the .beta.-blocker stably for a long period and a transdermally
absorbable preparation containing the composition.
[0010] Accordingly, the transdermally absorbable composition for
stabilizing .beta.-blocker according to the present invention
comprises the .beta.-blocker, a polymeric compound comprising an
amino group, a polyvalent carboxylic acid ester, a fatty acid
ester, and an acrylic polymer compound.
[0011] The transdermally absorbable preparation according to the
present invention also comprises at least said composition.
[0012] The stabilizing composition according to the present
invention has an effect of stabilizing even a .beta.-blocker which
tends to be decomposed and can inhibit the decomposition of the
.beta.-blocker in the composition remarkably even for a long period
of for example one month, so that the composition is convenient for
the storage of the transdermally absorbable preparation.
[0013] Furthermore, it is possible to retain a high dosage of the
.beta.-blocker suitable for the long term administration according
to the stabilizing composition of the present invention. Thus,
according to the transdermally absorbable preparation having a drug
containing layer which comprises the stabilizing composition, the
.beta.-blocker can be administrered to a living body stably for a
long period while controllong the decomposition of the
.beta.-blocker, and thus the blood concentration of the
.beta.-blocker is advantageously controlled within a certain range
for a long period.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a sectional view which illustrates one embodiment
of the transdermally absorbable preparation according to the
present invention.
[0015] FIG. 2 is a graph which illustrates the result of the in
vitro human skin permeation test with the transdermally absorbable
preparation according to the present invention.
THE DETAILED DESCRIPTION OF THE INVENTION
Definition
[0016] The "alkyl" as used herein means a linear, branched or
cyclic alkyl.
[0017] Also, the term "alcohol" as used herein means a linear,
branched or cyclic saturated or unsaturated alcohol.
[0018] Also, the term "higher alcohol" as used herein means an
alcohol having six or more carbon atoms.
[0019] Also, the term "polyvalent carboxylic acid" as used herein
means a bivalent or trivalent carboxylic acid having 6 to 10 carbon
atoms.
[0020] The composition of the .beta.-blocker according to the
present invention is used for stably retaining the .beta.-blocker
in the transdermally absorbable preparation as described above and
is characterized in that the composition comprises the
.beta.-blocker, a polymeric compound comprising an amino group, a
polyvalent carboxylic acid ester, a fatty acid ester and an acrylic
polymer compound. It is an unexpected fact that the above described
composition comprising these ingredients is capable of comprising a
high dosage of the .beta.-blocker and prominently stabilizing a
.beta.-blocker, which is liable to be decomposed.
[0021] In the present invention, the .beta.-blocker preferably
includes the compounds represented by the following formula (I) or
salts thereof.
##STR00001##
wherein R.sub.1 represents hydrogen or C1-4 alkylcarboxyl
group,
[0022] R.sub.2 represents a C1-6 alkyloxy C1-3 alkyl group
optionally substituted by a C1-5 alkyloxy group,
[0023] an aminocarbonyl C1-5 alkyl group,
[0024] a C1-6 alkylcarbonyl amino group, or
[0025] a C1-3 alkyloxycarbonyl C1-3 alkyl group.
[0026] The .beta.-blocker having the structure represented above
can be retained stably in the stabilizing composition according to
the present invention and includes a .beta.-blocker having a
.beta..sub.1-adrenaline blocking effect. The .beta.-blocker having
the .beta..sub.1-adrenaline blocking effect can be used also in
patients suffered from asthma including those whom the blockers of
.beta..sub.2-adrenaline receptor are contraindicant and can be
advantageously used also in patients concurrently suffered from
hypertension and heart disease.
[0027] Further, the C1-4 alkylcarboxyl group represented by R.sub.1
in the compound represented by the formula (I) is preferably a C1-3
alkylcarboxyl group, and more preferably an acetyl group.
[0028] Furthermore, the C1-6 alkyloxy C1-3 alkyl group represented
by R.sub.2 is preferably a C1-4 alkyloxy C1-2 alkyl group, and
further preferably a methoxyethyl group, an ethoxymethyl group or a
cyclopropylmethoxyethyl group.
[0029] Further, one or more hydrogens of the C1-6 alkyloxy C1-3
alkyl group represented by R.sub.2 may be substituted, and such
substituents include a C1-5 alkyloxy group, preferably a C1-3
alkyloxy group, more preferably a methoxy group, an ethoxy group,
an n-propoxy group or an isopropoxy group, further preferably an
isopropoxy group. In this connection, the C1-5 alkyloxy group as
the substituent in the C1-6 alkyloxy C1-3 alkyl group optionally
substituted is preferably substituted for one or more hydrogen
atoms in the terminal C1-6 alkyl.
[0030] Further, the aminocarbonyl C1-5 alkyl group represented by
R.sub.2 is preferably an aminocarbonyl C1-3 alkyl group, more
preferably an aminocarbonylmethyl group.
[0031] Further, the C1-6 alkylcarbonyl amino group represented by
R.sub.2 is preferably a C1-3 alkylcarbonylamino group, more
preferably a propylcarbonylamino group.
[0032] Further, a C1-3 alkyloxycarbonyl C1-3 alkyl group
represented by R.sub.2 is preferably a C1-2 alkyloxycarbonyl C1-2
alkyl group, more preferably a methyloxycarbonyl ethyl group.
[0033] Moreover, according to the preferred embodiment of the
present invention, in the compound represented by the formula
(I),
[0034] R.sub.1 represents hydrogen or a C1-3 alkylcarboxyl group,
and
[0035] R.sub.2 represents a C1-4 alkyloxy C1-2 alkyl group
optionally substituted by a C1-3 alkyloxy group, [0036] an
aminocarbonyl C1-3 alkyl group, [0037] a C1-3 alkylcarbonylamino
group, or [0038] a C1-2 alkyloxycarbonyl C1-2 alkyl group.
[0039] Further according to another embodiment of the present
invention, in the compound represented by the formula (I),
[0040] R.sub.1 represents hydrogen or an acetyl group, and
[0041] R.sub.2 represents a cyclopropylmethoxyethyl group, an
isopropoxyethoxymethyl group, a propylcarbonylamino group, an
aminocarbonylmethyl group, a methoxycarbonylethyl group or a
methoxyethyl group. The compound represented by the formula (I)
includes the .beta.-blockers such as betaxolol, bisoprolol,
acebutolol, atenolol, esmolol and metoprolol.
[0042] Further, in another preferable embodiment of the present
invention, in the compound represented by the formula (I), R.sub.1
represents hydrogen, and R.sub.2 represents a C1-4 alkyloxy C1-3
alkyl group optionally substituted by a C1-5 alkyloxy group.
[0043] The compound represented by the formula (I) in the
stabilizing composition according to the present invention can be
prominently stabilized, and its decomposition can be inhibited.
[0044] Further, according to another preferred embodiment, in the
compound represented by the formula (I), R.sub.2 represents a C1-4
alkyloxy C1-2 alkyl group optionally substituted by a C1-3 alkyloxy
group.
[0045] Furthermore, according to the other further preferred
embodiment, in the compound represented by the formula (I), R.sub.2
represents a cyclopropylmethoxyethyl group or an
isopropoxyethoxymethyl group. The compound represented by the
formula (I) includes .beta.-blockers such as betaxolol or
bisoprolol.
[0046] Moreover, the salts of the compound represented by the
formula (I) preferably include hydrochloride, phthalate, maleate,
fumarate, besylate, tosylate, citrate and succinate without
limitation thereto.
[0047] Furthermore, the stabilizing composition according to the
present invention can retain a high dosage of a .beta.-blocker
suitable for transdermal administration for a long period. The
content of such .beta.-blocker is preferably in the range of 10% by
mass or more, more preferably 10-40% by mass, further preferably
15-30% by mass.
[0048] Further, a polymeric compound comprising an amino group in
the composition according to the present invention is preferably a
C1-6 alkyl (meth)acrylate-C1-6 alkyl (meth)acrylate-di-C1-6
alkylamino C1-6 alkyl (meth)acrylate copolymer, more preferably a
C1-3 alkyl (meth)acrylate-C1-3 alkyl (meth)acrylate-di-C1-3
alkylamino C1-3 alkyl (meth)acrylate copolymer, further preferably
a methyl (meth)acrylate-butyl (meth)acrylate-dimethylaminoethyl
(meth)acrylate copolymer.
[0049] The molecular weight (Mw) and the molecular weight
distribution of the polymeric compound comprising an amino group
can be appropriately determined in consideration of the skin
permeation rate, storage period and the like of the .beta.-blocker.
Further, the molecular weight (Mw) and the molecular weight
distribution of the polymeric compound comprising an amino group
can be appropriately adjusted depending on the monomer amount, the
molar ratio of the monomer and a polymerization initiator, the
reaction temperature, the solvent and the like, and the molecular
weight can be determined for example by the viscosity method.
[0050] Furthermore, the content of the polymeric compound
comprising an amino group in the composition according to the
present invention is preferably in the range of 5 to 40% by mass,
more preferably 8 to 35% by mass, further preferably 12 to 26% by
mass.
[0051] Further the acrylic polymer compound in the present
invention is preferably a C1-10 alkyl (meth)acrylate-hydroxy C1-6
alkyl (meth)acrylate-C1-6 alkylepoxide (meth)acrylate-vinyl C1-6
carboxylate copolymer, more preferably a C5-8 alkyl
(meth)acrylate-hydroxy C1-3 alkyl (meth)acrylate-C1-3 alkylepoxide
(meth)acrylate-vinyl C1-3 carboxylate copolymer, further preferably
a 2-ethylhexyl acrylate-hydroxyethyl acrylate-glycidyl
(meth)acrylate-vinyl acetate copolymer.
[0052] Furthermore, the molecular weight (Mw) and the molecular
weight distribution of the acrylic polymer compound can be
appropriately determined in consideration of the skin permeation
rate, the storage period and the like of the .beta.-blocker. In
this connection, the molecular weight and the molecular weight
distribution of the acrylic polymer compound can be adjusted and
determined with the well known technique in the same manner as in
the polymeric compound comprising an amino group.
[0053] Further, the content of acrylic polymer compound in the
composition according to the present invention is preferably in the
range of 0.8 to 57% by mass, more preferably 12 to 26% by mass.
[0054] Furthermore, the polyvalent carboxylic acid ester in the
present invention is preferably a bivalant or trivalent carboxylic
acid C1-6 alkyl ester, more preferably a bivalant or trivalent
carboxylic acid C1-6 alkyl ester, further preferably a bivalant or
trivalent carboxylic acid C1-3 alkyl ester, further preferably a
citric acid tri-C1-3 alkyl ester or a sebacic acid di-C1-3 alkyl
ester, further preferably triethyl citrate or diethyl sebacate.
[0055] Furthermore, the content of the polyvalent carboxylic acid
ester in the composition according to the present invention is
preferably in the range of 5 to 20% by mass, more preferably 8 to
13% by mass.
[0056] In addition, the fatty acid ester in the present invention
is a C6-18 fatty acid C1-6 alkyl ester, preferably a C12-16 fatty
acid C1-3 alkyl ester. More specifically, the fatty acid ester
includes hexyl laurate, methyl myristate, isopropyl myristate,
isopropyl palmitate or ethy oleate, preferably isopropyl
myristate.
[0057] It is Preferable that the composition according to the
present invention further comprises a higher alcohol.
[0058] The higher alcohol is preferably a C6-20 alcohol. More
specifically, the higher alcohol includes cetyl alcohol, lauryl
alcohol, stearyl alcohol, isostearyl alcohol, myristyl alcohol,
oleyl alcohol, octyldodecanol or cetostearyl alcohol, preferably
oleyl alcohol.
[0059] Further, the content of the higher alcohol in the
composition according to the present invention can be set up in the
range of about 0 to 10% by mass, preferably 3 to 7% by mass.
[0060] Furthermore, according to one embodiment, the combination of
the preferred ingredients in the composition described above
comprises;
[0061] the .beta.-blocker including the compound represented by the
formula (I) or a salt thereof, wherein R.sub.1 represents hydrogen
or a C1-4 alkylcarboxyl group, R.sub.2 represents a C1-6 alkyloxy
C1-3 alkyl group optionally substituted by a C1-5 alkyloxy group,
an aminocarbonyl C1-5 alkyl group, a C1-6 alkylcarbonyl amino
group, or a C1-3 alkyloxy carbonyl C1-3 alkyl group;
[0062] the polymeric compound comprising an amino group including a
C1-6 alkyl(meth)acrylate-C1-6 alkyl(meth)acrylate-di-C1-6
alkylamino C1-6 alkyl(meth)acrylate copolymer,
[0063] the polyvalent carboxylic acid ester including a bivalent or
trivalent carboxylic acid C1-6 alkyl ester,
[0064] the fatty acid ester including a C4-18 fatty acid C1-6 alkyl
ester, and
[0065] the acrylic polymer compound including a C1-10
alkyl(meth)acrylate-hydroxy C1-6 alkyl(meth)acrylate-C1-6
alkylepoxide(meth)acrylate-vinyl C1-6 carboxylate copolymer.
[0066] Furthermore, according to the more preferred embodiment of
the present invention, in the composition described above
[0067] the .beta.-blocker represents said compound represented by
the formula (I) or a salt thereof,
[0068] the polymeric compound comprising an amino group represents
a C1-6 alkyl(meth)acrylate-C1-6 alkyl(meth)acrylate-di-C1-6
alkylamino C1-6 alkyl(meth)acrylate copolymer,
[0069] the polyvalent carboxylic acid ester represents a bivalent
or trivalent carboxylic acid C1-6 alkyl ester,
[0070] the fatty acid ester represents a C12-16 fatty acid C1-3
alkyl ester, and
[0071] the acrylic polymer compound represents a C1-10
alkyl(meth)acrylate-hydroxy C1-6 alkyl(meth)acrylate-C1-6
alkylepoxide(meth)acrylate-vinyl C1-6 carboxylate copolymer.
[0072] Furthermore, according to the further preferred embodiment
of the present invention, in the composition described above
[0073] the .beta.-blocker represents said compound represented by
the formula (I) or a salt thereof,
[0074] the polymeric compound comprising an amino group represents
a C1-6 alkyl(meth)acrylate-C1-6 alkyl(meth)acrylate-di-C1-6
alkylamino C1-6 alkyl(meth)acrylate copolymer,
[0075] the polyvalent carboxylic acid ester represents a citric
acid di-C1-3 alkyl ester or a sebacic acid tri-C1-3 alkyl
ester,
[0076] the fatty acid ester represents a C4-18 fatty acid C1-6
alkyl ester, and
[0077] the acrylic polymer compound represents a C1-10
alkyl(meth)acrylate-hydroxy C1-6 alkyl(meth)acrylate-C1-6
alkylepoxide(meth)acrylate-vinyl C1-6 carboxylate copolymer.
[0078] Furthermore, according to the further preferred embodiment
of the present invention, in the composition described above
[0079] the .beta.-blocker represents said compound represented by
the formula (I) or a salt thereof,
[0080] the polymeric compound comprising an amino group represents
a C1-6 alkyl (meth)acrylate-C1-6 alkyl (meth)acrylate-di-C1-6
alkylamino C1-6 alkyl (meth)acrylate copolymer,
[0081] the polyvalent carboxylic acid ester represents a citric
acid di-C1-3 alkyl ester or a sebacic acid tri-C1-3 alkyl
ester,
[0082] the fatty acid ester represents a C12-16 fatty acid C1-3
alkyl ester, and
[0083] the acrylic polymer compound represents a C5-8
alkyl(meth)acrylate-hydroxy C1-3 alkyl(meth)acrylate-C1-3
alkylepoxide(meth)acrylate-vinyl C1-3 carboxylate copolymer.
[0084] In addition, according to the further preferred embodiment
of the present invention, in the composition described above
[0085] the .beta.-blocker represents the compound represented by
the formula (I) or a salt thereof,
[0086] the polymeric compound comprising an amino group represents
a
methyl(meth)acrylate-butyl(meth)acrylate-dimethylaminoethyl(meth)acrylate
copolymer,
[0087] the polyvalent carboxylic acid ester represents triethyl
citrate,
[0088] the fatty acid ester represents isopropyl myristate, and
[0089] the acrylic polymer compound represents 2-ethylhexyl
acrylate-hydroxyethyl acrylate-glycidyl(meth)acrylate-vinyl acetate
copolymer.
[0090] Furthermore, according to the further preferred embodiment,
in the compound represented by the formula (I) in the composition
described above, R.sub.1 represents hydrogen or a C1-3
alkylcarboxyl group, and R.sub.2 represents a C1-4 alkyloxy C1-2
alkyl group optionally substituted by a C1-3 alkyloxy group, an
aminocarbonyl C1-3 alkyl group, a C1-3 alkylcarbonyl amino group,
or C1-2 alkyloxy carbonyl C1-2 alkyl group.
[0091] Furthermore, according to the further preferred embodiment,
in the composition described above, R.sub.1 represents hydrogen,
and R.sub.2 represents a C1-4 alkyloxy C1-3 alkyl group optionally
substituted by a C1-5 alkyloxy group.
[0092] Furthermore, according to the further preferred embodiment,
in the composition described above, R.sub.1 represents hydrogen,
and R.sub.2 represents a C1-4 alkyloxy C1-2 alkyl group optionally
substituted by a C1-3 alkyloxy group.
[0093] In addition, according to the further preferred embodiment,
in the composition described above, R.sub.1 represents hydrogen or
an acetyl group, and R.sub.2 represents a cyclopropylmethoxyethyl
group, an isopropoxyethoxymethyl group, a propylcarbonyl amino
group, an aminocarbonylmethyl group, a methoxycarbonylethyl group
or a methoxyethyl group.
[0094] In addition, according to the further preferred embodiment,
in the composition, R.sub.1 represents hydrogen, and R.sub.2
represents a cyclopropylmethoxyethyl group or an
isopropoxyethoxymethyl group. In this embodiment, the
.beta.-blocker corresponds to betaxolol or bisoprolol and are
remarkably stabilized and inhibited from decomposition, so that
these .beta.-blockers can be stored stably for a long period.
[0095] In this connection, the combination of the preferred
ingredients described above may further contain the aforementioned
higher alcohol, preferably a C6-20 alcohol, more preferably cetyl
alcohol, lauryl alcohol, stearyl alcohol, isostearyl alcohol,
myristyl alcohol, oleyl alcohol, octyl dodecanol or cetostearyl
alcohol, further preferably oleyl alcohol.
Transdermally Absorbable Preparation
[0096] The composition according to the present invention can
contain a high dosage of a .beta.-blocker as described above and
stably retain the .beta.-blocker for a long period. Thus, the use
of such composition as the drug containing layer of a transdermally
absorbable preparation is convenient for efficiently administering
the .beta.-blocker to the skin for a long period. Thus, according
to one embodiment, the transdermally absorbable preparation
comprises at least one drug containing layer comprising the
composition according to the present invention. In addition, such
drug containing layer may be used directly as a transdermally
absorbable preparation, but it is desirable to dispose on the
skin-contacting side a drug permeable polymer membrane which
ensures the controlled release of the .beta.-blocker into the skin,
taking the release control of the .beta.-blocker into account.
Furthermore, it is preferable to dispose the drug permeable polymer
membrane so that it is in direct contact with the skin in the
transdermally absorbable preparation. Such a disposition of the
drug permeable polymer membrane is advantageous to retaining the
skin permeation rate of a drug for a long period and efficiently
administering the drug to the skin. Thus, according to the
preferred embodiment, the transdermally absorbable preparation
comprises a laminate comprising, in the order from the skin side,
at least an outer membrane and the drug containing layer, and a
fixing means for fixing the laminate on the skin, wherein the drug
containing layer comprises the composition according to the present
invention and the outer membrane is a drug permeable polymer
membrane which ensures controlled release of the .beta.-blocker
into the skin and provided on the skin-contacting surface of the
laminate.
[0097] The preferred embodiment of the transdermally absorbable
preparation according to the present invention is illustrated with
reference to the scheme in the following.
[0098] FIG. 1 is a sectional view illustrating an embodiment of the
transdermally absorbable preparation according to the present
invention.
[0099] As shown in FIG. 1, the transdermally absorbable preparation
1 is provided with a laminate which comprises an outer membrane 3,
a drug containing layer 4 and a support layer 5, and a fixing means
7 for fixing the laminate 6 on the skin 2. In addition, the outer
membrane 3 comprises a drug permeable polymer membrane ensures
controlled release of the .beta.-blocker into the skin 2 and is
provided on the skin-contacting surface 8 of the laminate 6.
[0100] In addition, the fixing means 7 comprises the cover layer 9
covering the laminate 6 and the adhesive layer 10 for adhering the
cover layer 9 to the skin. The cover layer 9 covers the part except
the skin-contacting surface 8 of the laminate 6. In addition, the
adhesive layer 10 is disposed on the skin side of the cover layer
9. Furthermore, the adhesive layer 10 is disposed in the peripheral
and terminal regions in the skin-contacting surface 8 of the
laminate 6 and fixes the transdermally absorbable preparation 1 on
the skin 2. Such arrangement of the adhesive layer is advantageous
to avoiding the transfer of the components including the drug
resulting in the change of the physical properties of the adhesive
layer with the passage of time and retaining the stable adhesion of
the transdermally absorbable preparations to the skin.
[0101] In this connection, it is also possible to further coat a
part of the skin side of the drug permeable membrane with an
adhesive as far as the drug permeable membrane can be directly
contacted with the skin in order to assist the adhesion of the
transdermally absorbable preparation and the skin. The present
invention also involves such embodiment.
[0102] Furthermore, the drug permeable polymer membrane composing
the outer membrane in the transdermally absorbable preparation
according to the present invention is preferably a microporous
membrane having drug permeable pores, but the membrane is not
limited thereto as far as it ensures controlled release of the drug
to the skin. The microporous membrane is advantageous to adjusting
the drug release rate and controlling the blood concentration of
the drug within the safe and effective range. The pore size and the
pore density of the microporous membrane can be determined
appropriately in consideration of for example the desired skin
permeation rate of the .beta.-blocker. Also, the area of the skin
side of the drug permeable membrane can be appropriately determined
in consideration of for example the desired skin permeation rate,
application site and the like.
[0103] Furthermore, the preferred exampes of the constituent
materials of the drug permeable polymer membrane include EVA
(ethylene-vinyl acetate copolymer), polyethylene, polypropylene,
polyacrylonitrile, polymethyl methacrylate, and a combination
thereof, preferably polypropylene or EVA.
[0104] In addition, the adhesive layer is not particularly limited
to as far as it is a biocompatible material being capable of
bonding the skin and the transdermally absorbable preparation and
preferably includes polyacrylate, polydimethylsiloxane,
polyisobutylene or a combination thereof. Furthermore, to the
constituent materials of the adhesive layer may be added
appropriately for example a well known tackifier, and the like. The
aforementioned materials can be also used as an auxiliary adhesive
added to the surface of the drug permeable membrane.
[0105] Also, the contact area of the adhesive layer to the the skin
can be appropriately determined in consideration of the area of the
drug permeable membrane, the dosage period, the application site,
and the like.
[0106] In addition, the support layer may be stretchable or
non-stretchable. The specific material constituting the support
layer includes, but is not limited to as far as it can separate the
drug containing layer from the other materials, for instance, woven
fabric, unwoven fabric, PET (polyethylene terephthalate),
polyurethane, polyester, polyethylene or a composite material
thereof.
[0107] Also, for the cover, a similar material to that of the
support layer may be used.
Preparation Process
[0108] The preferred process for producing the transdermally
absorbable preparation according to the present invention is
described below.
[0109] The components of the stabilizing composition according to
the present invention are appropriately mixed in a solvent to
prepare a mixture containing the stabilizing composition in the
solvent. Next, the mixture is used as a plaster solution and coated
on a liner. Next, the plaster solution is dried at a temperature of
about 60 to 120.degree. C. to give a drug containing layer, on
which a support layer is laminated. Next, the liner is removed from
the drug containing layer, and the drug permeable membrane is
laminated on the side of the drug containing layer on which the
liner had been disposed to give a laminate. Next, a cover having an
adhesive layer disposed on one side is provided. Next, the adhesive
layer side of the cover and the support layer side of the laminate
are sticked together to give a transdermally absorbable
preparation. In this connection, the position and the size of the
adhesive layer are preliminarily configured so that the adhesive
layer covers the peripheral or terminal regions of one skin side of
the drug permeable membrane.
[0110] In the preparation process described above, the solvents
used in preparing the drug containing layer and the adhesive layer
include, for example, ethyl acetate, butyl acetate, toluene,
n-hexane, n-heptane, tetrahydrofuran, dimethylformamide, methanol
or ethanol.
Use
[0111] The transdermally absorbable preparation according to the
present invention can make a drug administered stably and
efficiently to a living body. Thus, the application period of the
transdermally absorbable preparation can be established to a long
period even on a single administration, preferably for 3 to 7 days,
more preferably about 7 days. Also, the .beta.-blocker in the
transdermally absorbable preparation is prominently stabilized, and
the transdermally absorbable preparation can be stably stored for
at least a month even in the absence of a desiccant.
[0112] Further, object disorders can be appropriately selected
depending on the kinds or characters of drugs, and the
administration schedule of a drug is appropriately determined
depending on the kind of the drug, the condition of a patient, the
administration period, the size of the drug, and the like by a
person skilled in the art.
[0113] Furthermore, the living bodies to which the transdermally
absorbable preparation according to the present invention is
applied include, for example, rabbit, dog or human, preferably
human.
EXAMPLE
[0114] The present invention is now described specifically with
reference to examples, but it is not limited to these examples.
Example 1
Formulation
TABLE-US-00001 [0115] TABLE 1 Component % by mass Betaxolol
hydrochloride (.beta.-blocker) 20 Aminoalkyl methacrylate copolymer
17.1 Triethyl citrate 10 Isopropyl myristate 10 Oley alcohol 5
Duro-Tak .RTM.387-2516 37.9 Outer membrane: Ethylene-vinyl acetate
copolymer membrane (CoTran .TM. 9702, 3M)
[0116] Betaxolol hydrochloride (LUSOCHIMICA S.P.A), aminoalkyl
methacrylate copolymer E (Degussa), triethyl citrate (Wako Pure
Chemical Industries, Ltd.), isopropyl myristate (Nikko Chemicals)
and oleyl alcohol (Kokyu Alcohol Kogyo Co., Ltd.) were provided in
the proportion described in the formulation and mixed by agitation
in an appropriate amount of ethyl acetate. To the mixture thus
obtained was added Duro-Tak.TM. 387-2516 (National Starch &
Chemical) in a proportion described in the formulation to give a
plaster solution.
[0117] The plaster solution was coated on a polyethylene
terephthalate liner and dried at 70.degree. C. for 15 minutes to
give a drug containing layer. The drug containing layer after
drying was adjusted to a weight of 100 g/m.sup.2.
[0118] Next, a support layer (Scotchpak.TM. 9732, 3M) was laminated
on the side opposite to the liner of the drug containing layer. The
liner was then removed from the drug containing layer and the drug
containing layer was sticked to an ethylene-vinyl acetate copolymer
membrane (outer membrane) to give a transdermally absorbable
preparation.
Example 2
Formulation
TABLE-US-00002 [0119] TABLE 2 Component % by mass Bisoprolol
fumarate(.beta.-blocker) 30 Aminoalkyl methacrylate copolymerE 24.1
Triethyl citrate 10 Isopropyl miristate 10 Duro-Tak .TM. 387-2516
25.9 Outer membrane: Microporous polypropylene membrane (Celgard
.TM. 2400, Celgard)
[0120] Bisoprolol fumarate (Parmachem Asia), aminoalkyl
methacrylate copolymer E (Degussa), triethyl citrate (Wako Pure
Chemical Industries, Ltd.), isopropyl myristate (Nikko Chemicals
Co., Ltd.) and oleyl alcohol (Kokyu Alcohol Kogyo Co., Ltd.) were
provided in the proportion described in the formulation and mixed
by agitation in an appropriate amount of ethyl acetate. To the
mixture thus obtained was added Duro-Tak.TM. 387-2516 (National
Starch & Chemical) in a proportion described in the formulation
to give a plaster solution.
[0121] The plaster solution was coated on a polyethylene
terephthalate liner and dried at 70.degree. C. for 15 minutes to
give a drug containing layer. The drug containing layer after
drying was adjusted to a weight of 100 g/m.sup.2.
[0122] Next, a support layer (Scotchpak.TM. 9732, 3M) was laminated
on the reverse side to the liner of the drug containing layer. The
liner was then removed from the drug containing layer and the drug
containing layer was sticked to a microporous polypropylene
membrane (outer membrane) to give a laminate (10 cm.sup.2). Next, a
foam tape (9773, 3M, 21.3 cm.sup.2) was provided as a cover, and
the adhesive layer side of the foam tape and the support layer side
of the laminate were sticked together to give a transdermally
absorbable preparation.
Example 3
Formulation
TABLE-US-00003 [0123] TABLE 3 Component % by mass Bisoprolol
fumarate (.beta.-blocker) 25 Aminoalkyl methacrylate copolymer E 20
Triethyl citrate 10 Isopropyl myristate 10 Oleyl alcohol 5 Duro-Tak
.TM. 387-2516 30 Outer membrane: Microporous polypropylene membrane
(Celgard .TM. 2400, Celgard)
[0124] Bisoprolol fumarate, aminoalkyl methacrylate copolymerE,
triethyl citrate, isopropyl myristate and coleyl alcohol were
provided in the proportion described in the formulation and mixed
by agitation in an appropriate amount of ethyl acetate. To the
mixture thus obtained was added Duro-Tak.TM. 387-2516 (National
Starch & Chemical) in a proportion described in the formulation
to give a plaster solution.
[0125] The plaster solution was coated on a polyethylene
terephthalate liner and dried at 70.degree. C. for 15 minutes to
give a drug containing layer. The drug containing layer after
drying was adjusted to a weight of 100 g/m.sup.2.
[0126] Next, a support layer (Scotchpak.TM. 9732, 3M) was laminated
on the reverse side to the liner of the drug containing layer. The
liner was then removed from the drug containing layer and the the
drug containing layer was sticked to a microporous polypropylene
membrane (outer membrane) to give a laminate (10 cm.sup.2). Next, a
foam tape (9773, 3M, 21.3 cm.sup.2) was provided as a cover, and
the adhesive layer side of the foam tape and the support layer side
of the laminate were sticked together to give a transdermally
absorbable preparation.
Referential Example 1
Formulation
TABLE-US-00004 [0127] TABLE 4 Component % by mass Betaxolol
hydrochloride (.beta.-blocker) 5 Diisopropanolamine 2 Liquid
paraffin 23.3 Oppanol B100 1.7 Oppanol B10 5.2
Styrene-isoprene-styrene block copolymer 16.3 Alicyclic saturated
hydrocarbon resin 46.5
[0128] Betaxolol hydrochloride, diisopropanolamine and liquid
paraffin were mixed by agitation in the proportion described in the
formulation to give a mixed solution. Next, a solution having
Oppanol B100 (BASF), Oppanol B10 (BASF), a styrene-isoprene-styrene
block copolymer (QUINTAC 3570C, Zeon Corporation) and an alicyclic
saturated hydrocarbon resin (ARKON P-100, Arakawa Chemical
Industries, Ltd.) dissolved in toluene was provided and added to
the mixed solution described above, and the mixture was agitated to
give a coating solution which contains the respective ingredients
in a proportion described in the formulation. The coating solution
was coated on a polyester liner and dried at 80.degree. C. for 15
minutes to give a drug containing layer. The drug containing layer
after drying was adjusted to a thickness of 100 .mu.m. Next, a
polyester film (Scotchpak.TM. 9732, 3M) as a support layer was
laminated on the reverse side to the liner of the drug containing
layer to give a matrix type transdermally absorbable
preparation.
Referential Example 2
Formulation
TABLE-US-00005 [0129] TABLE 5 Component % by mass Bisoprolol
fumarate (.beta.-blocker) 10 Triethanolamine 7.8 Liquid paraffin 5
Isopropyl myristate 5 Styrene-isoprene-styrene block copolymer 24.1
Alicyclic saturated hydrocarbon resin 48.2
[0130] Bisoprolol fumarate, triethanolamine, liquid paraffin and
isopropyl myristate were mixed by agitation in the proportion
described in the formulation to give a mixed solution. Next, a
solution having a styrene-isoprene-styrene block copolymer and an
alicyclic saturated hydrocarbon resin dissolved in toluene was
provided and added to the mixed solution described above, and the
mixture was agitated to give a coating solution which contains the
respective ingredients in a proportion described in the
formulation. The coating solution was coated on a polyester liner
and dried at 80.degree. C. for 15 minutes to give a drug containing
layer. The drug containing layer after drying was adjusted to a
thickness of 100 .mu.m. Next, a polyester film (Scotchpak.TM. 9732,
3M) as a support layer was laminated on the reverse side to the
liner of the drug containing layer to give a matrix type
transdermally absorbable preparation. In addition, the liner was
removed from the ransdermally absorbable preparation when the
preparation is used.
Test Example 1
In Vitro Human Skin Permeation Test
[0131] A part of a laminate obtained by bonding the drug containing
layer and the outer membrane in Examples 1 and 2 was placed on a
corneal layer of human epidermis so that the outer membrane is
arranged on the skin-contacting surface (application area: 4.5
cm.sup.2). The sample thus obtained was set up on a
flow-through-cell through which warm water was circulated so that
the skin surface is maintained at a temperature of about 32.degree.
C. Phosphate buffer physiological saline (pH 7.4) was used as a
receiver solution, which was collected every 2 hours in an amount
of 5 ml/hr for 24 hours. The flow rate of the solution thus
collected was measured, and the cumulative drug permeation amount
of a .beta.-blocker was measured by HPLC. The skin permeation rate
per hour was calculated from the results thus obtained.
[0132] The result is shown in FIG. 2. It has been confirmed that
both of the transdermally absorbable preparation in Examples 1 and
2 release the drug in an approximately constant skin permeation
rate for 1 week.
[0133] Further, the skin permeation rates (mcg/cm.sup.2/hr) in the
stationary state of the transdermally absorbable preparations in
Examples 1 and 2 are shown in Table 1.
TABLE-US-00006 TABLE 1 Preparation Skin permeation rate
(mcg/cm.sup.2/hr) Example 1 2.75 Example 2 10.50
Test Example 2
Drug Storage Stability Test
[0134] The transdermally absorbable preparations of Examples -1 to
3 were respectively enclosed in aluminum packaging bags for storing
at 40.degree. C. for one month. The transdermally absorbable
preparations of Referencial Examples 1 and 2 were respectively
enclosed in aluminum packaging bags for storing at 40.degree. C.
for one month in the same manner as those of Examples -1 to 3.
[0135] Then, the contents of the drug in the respective
transdermally absorbable preparations were measured by HPLC for
calculating the ratio of the drug content at the end of the test to
the drug content at the initiation of the test.
[0136] The results are shown in Table 2. About 5% of the decrease
in the content of the drug was observed in Referential Examples 1
and 2 at 1 month after initiating the test. On the other hand, the
content of the drug was in the range of 101.0-99.7 in Example -1 to
3, and no decrease in the content of the drug was observed.
[0137] In this connection, the standard error in this test was
about 2% (n=5).
TABLE-US-00007 TABLE 2 Content of drug (%) Example 1 101.0 Example
2 99.7 Example 3 101.0 Example 4 94.6 Example 5 94.7
Test Example 3
Drug Storage Stability Test
[0138] Storage stability at 40.degree. C. for 6 months was
confirmed in the same technique as in Test Example 2 with regard to
the transdermally absorbable preparations of Examples 1 and 3.
[0139] The results are shown in Table 3. The contents of the drugs
in Examples 1 and 3 were 100.1% and 98.4%, respectively, which were
higher than those in Referential Example 1 and 2 at 1 month after
initiating the test in Test Example 2.
[0140] In this connection, the standard error in this test was
about 2% (n=5).
TABLE-US-00008 TABLE 3 Content of drug (%) Example 1 100.0 Example
3 98.4
* * * * *