U.S. patent application number 15/473032 was filed with the patent office on 2017-07-13 for drug for preventing and/or treating polycystic kidney disease.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is OTSUKA PHARMACEUTICAL CO., LTD.. Invention is credited to Miki AIHARA, Hiroyuki FUJIKI, Shizuo KINOSHITA.
Application Number | 20170196877 15/473032 |
Document ID | / |
Family ID | 48670042 |
Filed Date | 2017-07-13 |
United States Patent
Application |
20170196877 |
Kind Code |
A1 |
FUJIKI; Hiroyuki ; et
al. |
July 13, 2017 |
DRUG FOR PREVENTING AND/OR TREATING POLYCYSTIC KIDNEY DISEASE
Abstract
An object of the present invention is to provide a combination
drug that has remarkably excellent preventive and/or therapeutic
effects on polycystic kidney disease. The present invention
provides a drug for preventing and/or treating polycystic kidney
disease comprising a combination of tolvaptan or a prodrug thereof
with a somatostatin derivative, and a method for treating
polycystic kidney disease using this drug.
Inventors: |
FUJIKI; Hiroyuki;
(Osaka-shi, JP) ; AIHARA; Miki; (Osaka-shi,
JP) ; KINOSHITA; Shizuo; (Osaka-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
48670042 |
Appl. No.: |
15/473032 |
Filed: |
March 29, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14402540 |
Nov 20, 2014 |
9636382 |
|
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PCT/JP2013/065637 |
May 30, 2013 |
|
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15473032 |
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61653524 |
May 31, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 38/31 20130101; A61P 13/00 20180101; A61K 31/55 20130101; A61K
9/0053 20130101; A61K 45/06 20130101; A61K 38/10 20130101; A61P
43/00 20180101; A61P 13/12 20180101; A61K 31/55 20130101; A61K
2300/00 20130101; A61K 38/31 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 38/31 20060101 A61K038/31; A61K 9/00 20060101
A61K009/00 |
Claims
1-11. (canceled)
12. A combination for suppressing disease progression of polycystic
kidney disease and/or treating polycystic kidney disease, wherein
said combination comprises tolvaptan or a prodrug thereof, and at
least one member selected from the group consisting of pasireotide,
lanreotide, vapreotide and a salt thereof.
13. The combination according to claim 12, wherein the dose of
tolvaptan or a prodrug thereof is less than an effective dose when
used alone.
14. The combination according to claim 12, wherein the combination
is in the form of separate formulations, and is a combination of an
oral preparation comprising tolvaptan or a prodrug thereof, and an
injectable preparation comprising at least one member selected from
the group consisting of pasireotide, lanreotide, vapreotide and a
salt thereof.
15. A kit for suppressing disease progression of polycystic kidney
disease and/or treating polycystic kidney disease, wherein said kit
comprises an oral preparation comprising tolvaptan or a prodrug
thereof, and an injectable preparation comprising at least one
member selected from the group consisting of pasireotide,
lanreotide, vapreotide and a salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a drug for preventing
and/or treating polycystic kidney disease (PKD).
BACKGROUND ART
[0002] Polycystic kidney disease is classified into ADPKD
(autosomal dominant polycystic kidney disease) and ARPKD (autosomal
recessive polycystic kidney disease). In both types of polycystic
kidney disease, many cysts develop in the cortex and medulla of the
kidney, leading to kidney dysfunction accompanied by substantial
atrophy and fibrosis. As the disease progresses, the kidneys
develop hypertrophy, leading to kidney failure requiring
dialysis.
[0003] In cyst epithelial cells wherein cysts develop from tubular
cells, cyclic AMP (cAMP) activates protein kinase A (PKA), and a
series of MAP kinase (MAPK) pathways are activated to induce cell
proliferation. In the cyst epithelial cells, the expression of
vasopressin receptor (V2R) is enhanced and adenylate cyclase
activity is elevated, which further increases cAMP levels and
accelerates cell proliferation.
[0004] Vasopressin receptor antagonists have been reported to have
complete response in animal models of polycystic kidney disease,
and tolvaptan is advancing in clinical trials (see, for example,
Patent Literature (PTL) 1 and Non-patent Literature (NPL) 1, 2, and
3).
[0005] Octreotide, which is a somatostatin derivative that
suppresses adenylate cyclase activity, is also expected to be
useful as an agent for treating ADPKD, and clinical test results
therefor have recently been reported (see Non-patent Literature
(NPL) 4).
CITATION LIST
Patent Literature
[0006] PTL 1: JP4-154765A
Non-Patent Literature
[0007] NPL 1: Nat. Med., 2003, 9(10):1323-6
[0008] NPL 2: J. Am. Soc. Nephrol., 2005, 16:846-851
[0009] NPL 3: Clin. J. Am. Soc. Nephrol. 2008, 3:1212-1218
[0010] NPL 4: J. Am. Soc. Nephrol., 2010, 21:1052-1061
SUMMARY OF INVENTION
Technical Problem
[0011] An object of the present invention is to provide a
combination drug that has remarkably excellent preventive and/or
therapeutic effects on polycystic kidney disease.
Solution to Problem
[0012] To solve the above problem, the present inventors conducted
extensive research on combination drugs that can remarkably
increase preventive and/or therapeutic effects on polycystic kidney
disease. As a result, the inventors confirmed that the combined use
of tolvaptan and a somatostatin derivative, octreotide, can produce
remarkable therapeutic effects (e.g., reduction of kidney weight)
on polycystic kidney disease, compared to the use of either
compound alone. Further, the inventors confirmed that a combination
of tolvaptan and the somatostatin derivative can provide remarkable
therapeutic effects on polycystic kidney disease, even when the
dose of the tolvaptan and/or the somatostatin derivative is so low
as to be ineffective if either of the compounds is used alone. As a
result of further research based on this finding, the present
invention has been accomplished.
[0013] More specifically, the present invention provides the
following combination drugs.
[0014] Item 1. A drug for preventing and/or treating polycystic
kidney disease comprising a combination of tolvaptan or a prodrug
thereof with a somatostatin derivative.
[0015] Item 2. The drug according to Item 1 comprising a
combination of a pharmaceutical composition (a pharmaceutical
preparation) comprising tolvaptan or a prodrug thereof with a
pharmaceutical composition (a pharmaceutical preparation)
comprising a somatostatin derivative.
[0016] Item 3. The drug according to Item 1 or 2 comprising a low
dose of tolvaptan or a prodrug thereof that would be ineffective if
used alone.
[0017] Item 4. The drug according to any one of Items 1 to 3
wherein the somatostatin derivative is octreotide, pasireotide,
lanreotide, vapreotide, or a salt thereof.
[0018] Item 5. The drug according to any one of Items 1 to 4 which
is a combination of an orally administered drug comprising
tolvaptan or a prodrug thereof and an injectable preparation
comprising a somatostatin derivative.
[0019] Item 6. The drug according to Item 5 wherein the injectable
preparation comprising the somatostatin derivative is a
subcutaneously administered drug.
[0020] Item 7. The drug according to Item 5 wherein the injectable
preparation comprising the somatostatin derivative is an
intramuscularly administered drug.
[0021] Item 8. Use of a combination of tolvaptan or a prodrug
thereof with a somatostatin derivative in the manufacture of a drug
for preventing and/or treating polycystic kidney disease.
[0022] Item 9. A drug comprising a combination of tolvaptan or a
prodrug thereof with a somatostatin derivative for use in the
prevention and/or treatment of polycystic kidney disease.
[0023] Item 10. A method for treating polycystic kidney disease,
comprising administering tolvaptan or a prodrug thereof in
combination with a somatostatin derivative to a polycystic kidney
disease patient.
[0024] Item 11. The method according to Item 10 wherein the
tolvaptan or prodrug thereof is orally administered and the
somatostatin derivative is subcutaneously or intramuscularly
administered to the polycystic kidney disease patient.
[0025] Item 12. A kit for preventing and/or treating polycystic
kidney disease comprising an orally administered drug comprising
tolvaptan or a prodrug thereof and an injectable preparation (in
particular, a subcutaneously administered drug or an
intramuscularly administered drug) comprising a somatostatin
derivative.
[0026] Item 13. The drug according to any one of Items 1 to 7
wherein the tolvaptan or a prodrug thereof is tolvaptan and the
somatostatin derivative is octreotide.
[0027] Item 14. The use according to Item 8 wherein the tolvaptan
or a prodrug thereof is tolvaptan and the somatostatin derivative
is octreotide.
[0028] Item 15. The drug according to item 9 wherein the tolvaptan
or a prodrug thereof is tolvaptan and the somatostatin derivative
is octreotide.
[0029] Item 16. The method according to Item 10 or 11 wherein the
tolvaptan or a prodrug thereof is tolvaptan and the somatostatin
derivative is octreotide.
[0030] Item 17. The kit according to Item 12 wherein the tolvaptan
or a prodrug thereof is tolvaptan and the somatostatin derivative
is octreotide.
Advantageous Effects of Invention
[0031] The drug comprising a combination of tolvaptan or a prodrug
thereof with a somatostatin derivative according to the present
invention provides remarkable therapeutic effects on polycystic
kidney disease (e.g., a kidney weight increase-suppressing effect,
a renal function-improving effect, etc.), compared to either
compound used alone. A combination of tolvaptan or a prodrug
thereof with a somatostatin derivative provides remarkable
therapeutic effects on polycystic kidney disease, even when the
dose of tolvaptan or a prodrug thereof and/or the somatostatin
derivative is so low as to be ineffective if either compound is
used alone.
[0032] Because the combination drug of the present invention can
thereby maintain drug efficacy while reducing side effects, the
provision of high therapeutic effects while maintaining the quality
of life (QOL) of polycystic kidney disease patients can be
expected.
DESCRIPTION OF EMBODIMENTS
[0033] A feature of the drug for preventing and/or treating
polycystic kidney disease according to the present invention is
that it comprises a combination of tolvaptan or a prodrug thereof
with a somatostatin derivative.
1. Tolvaptan and a Prodrug Thereof
[0034] Tolvaptan is the common name for
7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-t-
etrahydro-1H-benzoazepine, represented by Formula (1).
##STR00001##
[0035] Tolvaptan contains a hydroxy-bonded carbon atom as an
asymmetric carbon, as shown in Formula (1). Therefore, tolvaptan
has a pair of enantiomers (R- and S-enantiomers) based on the
asymmetric carbon. The term "tolvaptan" is used to include R
enantiomer, S enantiomer, and a mixture of the two enantiomers in
any proportion. Tolvaptan is preferably R enantiomer, S enantiomer,
or a racemic compound (an equal mixture of R enantiomer and S
enantiomer); and is more preferably a racemic compound.
[0036] Tolvaptan may be crystalline, amorphous, or a mixture of the
two. When crystals have two or more polymorphisms, tolvaptan
includes all of the polymorphisms.
[0037] Tolvaptan may be such that one or more atoms in the molecule
of the tolvaptan are replaced by one or more isotopes thereof.
Examples of such isotopes include deuterium (.sup.2H), tritium
(.sup.3H), .sup.13C, .sup.14N, .sup.18O, and the like.
[0038] Tolvaptan may be in the form of, for example, an anhydride,
a solvate (e.g., a hydrate, an alcoholate, etc.), a salt, or
co-crystals.
[0039] Tolvaptan may be a prodrug. The prodrug is a compound
obtained by modifying an active compound (tolvaptan) in
consideration of improved solubility in water, improved
stabilization, improved bioavailability, etc.
[0040] An example of a prodrug is a compound produced by
phosphorylation of the hydroxy group of tolvaptan. Specific
examples thereof include a benzazepine compound represented by the
following Formula (1a) or a salt thereof, which is disclosed in
JP2009-52197A.
##STR00002##
(wherein R is a hydrogen atom, a hydroxy group optionally having a
protecting group, a mercapto group optionally having a protecting
group, or an amino group optionally having one or two protecting
groups; R.sup.a is a hydrogen atom or a hydroxy-protecting group;
and X is an oxygen atom or a sulfur atom).
[0041] In Formula (1a), there is no particular limitation on the
"protecting group" for the hydroxy group optionally having a
protecting group, the mercapto group optionally having a protecting
group, or the amino group optionally having one or two protecting
groups, represented by R. Typical examples of protecting groups
include lower alkyl groups (for example, C.sub.1-6 alkyl groups,
such as methyl and ethyl), phenyl-lower alkyl groups (for example,
phenyl-C.sub.1-6 alkyl groups, such as benzyl and phenethyl), lower
alkoxycarbonyl groups (for example, C.sub.1-6 alkoxycarbonyl
groups, such as methoxycarbonyl, ethoxycarbonyl, and
tert-butoxycarbonyl), and the like.
[0042] Examples of the hydroxy protecting group represented by
R.sup.a in Formula (1a) are those mentioned above as examples of
the "protecting group" included in R.
[0043] Other examples of prodrugs include a compound obtained by
acylating the hydroxy group of tolvaptan. Specific examples thereof
include a benzazepine compound represented by the following formula
(1b) or a salt thereof, which are disclosed in WO2009/001968
(JP2010-531293A).
##STR00003##
wherein R.sup.1 is a group of (1-1) to (1-7) below: [0044] (1-1) a
--CO--(CH.sub.2).sub.n--COR.sup.2 group (wherein n is an integer of
1 to 4, R.sup.2 is (2-1) a hydroxy group; (2-2) a lower alkoxy
group optionally substituted with a hydroxy group, a lower alkanoyl
group, a lower alkanoyloxy group, a lower alkoxycarbonyloxy group,
a cycloalkyloxycarbonyloxy group, or
5-methyl-2-oxo-1,3-dioxol-4-yl; or (2-3) an amino group optionally
substituted with a hydroxy-lower alkyl group); [0045] (1-2) a
--CO--(CH.sub.2).sub.m--NR.sup.3R.sup.4 group [0046] (wherein m is
an integer of 0 to 4, R.sup.3 is a hydrogen atom or a lower alkyl
group, R.sup.4 is (4-1) a hydrogen atom; (4-2) a lower alkyl group
optionally substituted with a halogen atom, a lower alkylamino
group, a lower alkoxycarbonyl group, or
5-methyl-2-oxo-1,3-dioxol-4-yl; or (4-3) a lower alkoxycarbonyl
group optionally substituted with a halogen atom, a lower
alkanoyloxy group, or 5-methyl-2-oxo-1,3-dioxol-4-yl, R.sup.3 and
R.sup.4 may form a 5- or 6-membered saturated heterocyclic ring by
bonding R.sup.3 and R.sup.4 to each other, together with the
nitrogen atom to which R.sup.3 and R.sup.4 bond, directly or via a
nitrogen atom or oxygen atom, the heterocyclic ring being
optionally substituted with (4-4) a lower alkyl group (the lower
alkyl group being optionally substituted with a hydroxy-lower
alkoxy group); (4-5) a lower alkoxycarbonyl group; (4-6) an
alkylcarbonyl group (the alkyl group being optionally substituted
with a carboxyl group or a lower alkoxycarbonyl group); (4-7) an
arylcarbonyl group; or (4-8) a furylcarbonyl group); [0047] (1-3) a
--CO--(CH.sub.2).sub.p--O--CO--NR.sup.5R.sup.6 group [0048]
(wherein p is an integer of 1 to 4, R is a lower alkyl group, and
R.sup.6 is a lower alkoxycarbonyl-lower alkyl group); [0049] (1-4)
a --CO--(CH.sub.2).sub.q--X--R.sup.7 group [0050] (wherein q is an
integer of 1 to 4, X is an oxygen atom, a sulfur atom, or a
sulfonyl group, and R.sup.7 is a carboxy-lower alkyl group, or a
lower alkoxycarbonyl-lower alkyl group); [0051] (1-5) a
--CO--R.sup.3 group [0052] (wherein R.sup.8 is (8-1) an alkyl group
optionally substituted with a halogen atom, a lower alkanoyloxy
group, or a phenyl group (the phenyl group being substituted with a
dihydroxyphosphoryloxy group in which the hydroxy groups are
optionally substituted with benzyl groups, and a lower alkyl
group), (8-2) a lower alkoxy group substituted with a halogen atom,
a lower alkanoyloxy group, or a dihydroxyphosphoryloxy group, (8-3)
a pyridyl group, or (8-4) a lower alkoxyphenyl group); [0053] (1-6)
a lower alkyl group substituted with a group selected from the
group consisting of lower alkylthio groups, a
dihydroxyphosphoryloxy group, and lower alkanoyloxy groups; and
[0054] (1-7) an amino acid or peptide residue optionally protected
with one or more protecting groups.
[0055] In Formula (1b), the term "lower" refers to "C.sub.1-6",
unless otherwise specified.
[0056] Examples of lower alkanoyl groups include straight or
branched C.sub.2-6 alkanoyl groups, such as acetyl, n-propionyl,
n-butyryl, isobutyryl, n-pentanoyl, tert-butylcarbonyl, and
n-hexanoyl.
[0057] Examples of lower alkanoyloxy groups include straight or
branched C.sub.2-6 alkanoyloxy groups, such as acetyloxy,
n-propionyloxy, n-butyryloxy, isobutyryloxy, n-pentanoyloxy,
tert-butylcarbonyloxy, and n-hexanoyloxy.
[0058] Examples of lower alkoxycarbonyloxy groups include
alkoxycarbonyloxy groups in which the alkoxy moiety is a straight
or branched C.sub.1-6 alkoxy group, such as methoxycarbonyloxy,
ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy,
n-buthoxycarbonyloxy, isobuthoxycarbonyloxy,
tert-buthoxycarbonyloxy, sec-buthoxycarbonyloxy,
n-pentyloxycarbonyloxy, neopentyloxycarbonyloxy,
n-hexyloxycarbonyloxy, isohexyloxycarbonyloxy, and 3-methyl
pentyloxycarbonyloxy.
[0059] Examples of cycloalkyloxycarbonyloxy groups include
cycloalkyloxycarbonyloxy groups in which the cycloalkyl moiety is a
C.sub.3-8 cycloalkyl group, such as cyclopropyloxycarbonyloxy,
cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy,
cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy, and
cyclooctyloxycarbonyloxy.
[0060] Examples of cycloalkylcarbonyl groups include
cycloalkylcarbonyl groups in which the cycloalkyl moiety is a
C.sub.3-8 cycloalkyl group, such as cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
cycloheptylcarbonyl, and cyclooctylcarbonyl.
[0061] Examples of lower alkoxy groups include straight or branched
C.sub.1-6 alkoxy groups, such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy,
n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy,
and 3-methylpentyloxy.
[0062] Examples of hydroxy-lower alkyl groups include straight or
branched C.sub.1-6 alkyl groups having one to three hydroxy groups,
such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl,
3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl,
3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl,
6-hydroxyhexyl, 3,3-dimethyl-3-hydroxypropyl,
2-methyl-3-hydroxypropyl, and 2,3,4-trihydroxybutyl.
[0063] Examples of alkyl groups include straight or branched
C.sub.1-10 alkyl groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl,
neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
[0064] Examples of lower alkyl groups include straight or branched
C.sub.1-6 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl,
neopentyl, n-hexyl, isohexyl, and 3-methylpentyl.
[0065] Examples of halogen atoms include fluorine, chlorine,
bromine, and iodine.
[0066] Examples of lower alkylamino groups include amino groups
substituted with one to two straight or branched C.sub.1-6 alkyl
groups, such as methylamino, ethylamino, n-propylamino,
isopropylamino, n-butylamino, tert-butylamino, n-pentylamino,
n-hexylamino, dimethylamino, diethylamino, di-n-propylamino,
di-n-butylamino, di-n-pentylamino, di-n-hexylamino,
N-methyl-N-ethylamino, N-ethyl-N-n-propylamino,
N-methyl-N-n-butylamino, and N-methyl-N-n-hexylamino.
[0067] Examples of lower alkoxycarbonyl groups include
alkoxycarbonyl groups in which the alkoxy moiety is a straight or
branched C.sub.1-6 alkoxy group, such as methoxycarbonyl,
ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,
n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,
sec-butoxycarbonyl, n-pentyloxycarbonyl, neopentyloxycarbonyl,
n-hexyloxycarbonyl, isohexyloxycarbonyl, and
3-methylpentyloxycarbonyl.
[0068] Examples of 5- or 5-membered saturated heterocyclic rings
formed by bonding R.sup.3 and R.sup.4 to each other, together with
the nitrogen atom to which R.sup.3 and R.sup.4 bond, directly or
via a nitrogen atom or oxygen atom include pyrrolidine,
imidazolidine, piperazine, piperidine, and morpholine.
[0069] Examples of hydroxy-lower alkoxy groups include
hydroxyalkoxy groups that have one or two hydroxy groups, the
alkoxy moiety being a straight or branched C.sub.1-6 alkoxy group,
such as hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy,
3-hydroxypropoxy, 4-hydroxybutoxy, 5-hydroxypentyloxy,
6-hydroxyhexyloxy, 1,1-dimethyl-2-hydroxyethoxy, and
2-methyl-3-hydroxypropoxy.
[0070] Examples of alkylcarbonyl groups include alkylcarbonyl
groups in which the alkyl moiety is a straight or branched
C.sub.1-20 alkyl group, such as methylcarbonyl, ethylcarbonyl,
n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,
isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl,
n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl,
n-hexylcarbonyl, isohexylcarbonyl, 3-methylpentylcarbonyl,
n-heptylcarbonyl, n-octylcarbonyl, n-nonylcarbonyl,
n-decylcarbonyl, n-undecylcarbonyl, n-dodecylcarbonyl,
n-tridecylcarbonyl, n-tetradecylcarbonyl, n-pentadecylcarbonyl,
n-hexadecylcarbonyl, n-heptadecylcarbonyl, n-octadecylcarbonyi,
n-nonadecylcarbonyl, and n-icosylcarbonyl.
[0071] Examples of arylcarbonyl groups include phenylcarbonyl and
(1- or 2-)naphthylcarbonyl.
[0072] Examples of furylcarbonyl groups include (2- or
3-)furylcarbonyl.
[0073] Examples of lower alkoxycarbonyl-lower alkyl groups include
alkoxycarbonylalkyl groups in which the alkoxy moiety is a straight
or branched C.sub.1-6 alkoxy group, and the alkyl moiety is a
straight or branched C.sub.1-6 alkyl group, such as
methoxycarbonylmethyl, ethoxycarbonylmethyl,
2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,
1-ethoxycarbonylethyl, 3-methoxycarbonylpropyl,
3-ethoxycarbonylpropyl, 4-ethoxycarbonyibutyl, 5-isopropoxycarbonyl
pentyl, 6-n-propoxycarbonylhexyl,
1,1-dimethyl-2-n-butoxycarbonylethyl,
2-methyl-3-tert-butoxycarbonylpropyl, 2-n-pentyloxycarbonylethyl,
and n-hexyloxycarbonylmethyl.
[0074] Examples of carboxy-lower alkyl groups include carboxyalkyl
groups in which the alkyl moiety is a straight or branched
C.sub.1-6 alkyl group, such as carboxymethyl, 2-carboxyethyl,
1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl,
6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, and
2-methyl-3-carboxypropyl.
[0075] Examples of lower alkoxyhenyl groups include alkoxyphenyl
groups in which the alkoxy moiety is a straight or branched
C.sub.1-6 alkoxy group, such as methoxyphenyl, ethoxyphenyl,
n-propoxyphenyl, isopropoxyphenyl, n-butoxyphenyl, isobutoxyphenyl,
tert-butoxyphenyl, sec-butoxyphenyl, n-pentyloxyphenyl,
isopentyloxyphenyl, neopentyloxyphenyl, n-hexyloxyphenyl,
isohexyloxyphenyl, and 3-methylpentyloxyphenyl.
[0076] Examples of lower alkylthio groups include straight or
branched C.sub.1-6 alkylthio groups, such as methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio, tert-butylthio,
n-pentylthio, and n-hexylthio.
[0077] Examples of amino acid or peptide residues include amino
acid residues such as alanyl, phenylalanyl, sarcosyl, valyl,
leucyl, isoleucyl, prolyl, N-ethylglycyl, N-propylglycyl,
N-isopropylglycyl, N-butylglycyl, N-tert-butylglycyl,
N-pentylglycyl, N-hexylglycyl, N,N-diethylglycyl,
N,N-dipropylglycyl, N,N-dibutylglycyl, N,N-dipentylglycyl,
N,N-dihexylglycyl, N-methyl-N-ethylglycyl, N-methyl-N-propylglycyl,
N-methyl-N-butylglycyl, N-methyl-N-pentylglycyl, and
N-methyl-N-hexylglycyl; and peptide residues such as
sarcosyl-glycyl, glycyl-glycyl, glycyl-sarcosyl, sarcosyl-sarcosyl,
alanyl-glycyl, phenylalanyl-glycyl, phenylalanyl-phenylalanyl,
glycyl-glycyl-glycyl, N-ethylglycyl-glycyl, N-propylglycyl-glycyl,
N,N-dimethylglycyl-glycyl, N,N-diethylglycyl-glycyl,
N-methyl-N-ethylglycyl-glyoyl, sarcosyl-glycyl-glycyl,
N-ethylglycyl-glycyl-glycyl, and
N,N-dimethylglycyl-glycyl-glycyl.
[0078] Examples of protecting groups for amino acids or peptides
include those usually used to protect amino groups of amino acids
or peptides, such as tert-butoxycarbonyl, benzyloxycarbonyl,
fluorenylmethoxycarbonyl, and acetyl.
[0079] In this specification, a prodrug of tolvaptan (in
particular, a compound of Formula (1a) and/or a compound of Formula
(1b)) can be used together with or substituted for tolvaptan. In
the present invention, tolvaptan is preferable.
2. Somatostatin Derivative
[0080] The term "somatostatin derivative" refers to somatostatin, a
compound comprising an amino acid sequence (Phe-Trp-Lys-Thr)
essential for the physiological activity of somatostatin; or salts
thereof. Specific examples thereof include somatostatin,
octreotide, pasireotide, lanreotide, vapreotide, and the like. Such
compounds can be used singly, or in a combination of two or more.
Octreotide is preferable.
[0081] Octreotide refers to a cyclic polypeptide represented by
Formula (2), and is the common name for
(-)-D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-thre-
onyl-N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl]-L-cysteinamide
cyclic (2.fwdarw.7) disulfide.
##STR00004##
[0082] The somatostatin derivative may form a salt with a
pharmaceutically acceptable acid. Examples of such acids include
inorganic acids such as hydrochloric acid, hydrobromic acid, nitric
acid, sulfuric acid, and phosphoric acid; and organic acids such as
methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric
acid, tartaric acid, maleic acid, fumaric acid, malic acid, and
lactic acid. The salt of the somatostatin derivative is preferably
hydrochloride or acetate, and more preferably diacetate of
octreotide. This is commercially available under the trade name
"Sandostatin" (a product of Novartis Pharma K.K.).
3. Pharmaceutical Preparation
[0083] A feature of the drug for preventing and/or treating
polycystic kidney disease according to the present invention is
that it comprises a combination of tolvaptan or a prodrug thereof
with a somatostatin derivative. The combination is preferably a
combination of tolvaptan with a somatostatin derivative. A
combination of tolvaptan with octreotide, a combination of
tolvaptan with pasireotide, a combination of tolvaptan with
lanreotide, or a combination of tolvaptan with vapreotide is more
preferable. A combination of tolvaptan with octreotide is even more
preferable. These combinations apply to the entire invention.
[0084] The drug of the present invention may be in the form of a
single formulation (a mixture) comprising tolvaptan or a prodrug
thereof with a somatostatin derivative; or in the form of separate
formulations (concomitants), one of the formulations comprising
tolvaptan or a salt thereof, and the other comprising a
somatostatin derivative. The drug is preferably concomitants.
[0085] One example of such concomitants is a combination of a
pharmaceutical composition (a pharmaceutical preparation)
comprising tolvaptan or a prodrug thereof with a pharmaceutical
composition (a pharmaceutical preparation) comprising a
somatostatin derivative.
[0086] The pharmaceutical preparation comprising a combination of
tolvaptan or a prodrug thereof with a somatostatin derivative may
be a mixture or concomitants, and the dosage form of the
pharmaceutical preparation can be suitably selected from those
described below.
[0087] The pharmaceutical preparation can be produced by
incorporating tolvaptan or a prodrug thereof and/or a somatostatin
derivative by a conventional method using a commonly used diluent
and/or excipient, such as a filler, an extender, a binder, a
humectant, a disintegrator, a surfactant, and a lubricant.
[0088] The form of the pharmaceutical preparation can be suitably
selected from various forms according to the therapeutic purpose.
Typical examples of such forms include tablets, pills, powders,
liquids, suspensions, emulsions, granules, capsules, suppositories,
ointments, injections (solutions, suspensions, emulsions, etc.),
and the like.
[0089] To form tablets, various carriers known in the art can be
used. Examples of such carriers include excipients such as lactose,
sucrose, sodium chloride, glucose, urea, starch, calcium carbonate,
kaolin, and crystalline cellulose; binders such as water, ethanol,
propanol, simple syrup, glucose solution, starch solution, gelatin
solution, carboxymethyl cellulose, shellac, methylcellulose,
potassium phosphate, and polyvinylpyrrolidone; disintegrators such
as dry starch, sodium alginate, agar powder, laminaran powder,
sodium hydrogen carbonate, calcium carbonate, polyoxyethylene
sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid
monoglyceride, starch, and lactose; disintegration inhibitors such
as sucrose, stearin, cacao butter, and hydrogenated oil; absorption
promoters such as quaternary ammonium salts and sodium lauryl
sulfate; humectants such as glycerol and starch; adsorbents such as
starch, lactose, kaolin, bentonite, and colloidal silica; and
lubricants such as purified talc, stearic acid salts, boric acid
powder, and polyethylene glycol.
[0090] The tablets, if desired, can be coated with a general
coating material to give coated tablets. Examples of such coated
tablets include sugar-coated tablets, gelatin-coated tablets,
enteric coated tablets, film-coated tablets, bilayer tablets, and
multilayer tablets.
[0091] To form pills, various carriers known in the art can be
used. Examples of such carriers include excipients such as glucose,
lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin,
and talc; binders such as gum arabic powder, tragacanth powder,
gelatin, and ethanol; and disintegrants such as laminaran and
agar.
[0092] To form suppositories, various carriers known in the art can
be used. Examples of such carriers include polyethylene glycol,
cacao butter, higher alcohols, higher alcohol esters, gelatin, and
semisynthetic glycerides.
[0093] Injections are preferably prepared in the form of solutions,
emulsions, or suspensions that are sterilized and isotonic with
blood. To form such solutions, emulsions, and suspensions using
tolvaptan or a prodrug thereof and/or a somatostatin derivative,
any diluents commonly used in the art can be used. Examples of such
diluents include water, lactic acid aqueous solution, ethanol,
propylene glycol, ethoxylated isostearyl alcohol, polyoxylated
isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester.
In this case, an isotonizing agent, such as sodium chloride,
glucose, mannitol, or glycerol, may be incorporated into such a
pharmaceutical preparation in an amount sufficient for making the
preparation isotonic. Further, commonly used pH adjusters,
solubilizers, buffers, soothing agents, etc., as well as coloring
agents, preservatives, flavors, sweetening agents, and/or other
medicines may be added, if necessary.
[0094] The amount of tolvaptan or a prodrug thereof and/or
somatostatin derivative in the pharmaceutical preparation of the
invention is not particularly limited insofar as it is a
therapeutically effective amount as a combination drug, and can be
suitably selected from a wide range. It is generally preferable
that tolvaptan or a prodrug thereof and/or a somatostatin
derivative are contained in the pharmaceutical preparation in a
proportion of about 0.01 to about 70 wt %. For example, when
concomitants are used as the combination drug, the pharmaceutical
preparation comprising tolvaptan or a prodrug thereof typically
comprises the tolvaptan or the prodrug thereof in an amount of 0.01
to 70 wt. %, and the pharmaceutical preparation comprising a
somatostatin derivative typically comprises the somatostatin
derivative in an amount of 0.01 to 70 wt. %.
4. Administration Method and Dosage
[0095] The method of administration (administration route) of the
pharmaceutical preparation of the invention is not particularly
limited. This preparation can be administered by a method suitable
for the dosage form, the patient's age and sex, the status of the
disease, and other conditions. For example, tablets, pills,
liquids, suspensions, emulsions, granules, and capsules are
administered orally. Injections are intravenously administered
singly or as a mixture with a general injection transfusion, such
as glucose solution or amino acid solution, or singly administered
intramuscularly, intracutaneously, subcutaneously or
intraperitoneally, as required. The suppositories are administered
intrarectally.
[0096] Typical examples of the combination drug of the present
invention are concomitants. One example of such concomitants is a
combination of a pharmaceutical composition (a pharmaceutical
preparation) comprising tolvaptan or a prodrug thereof with a
pharmaceutical composition (a pharmaceutical preparation)
comprising a somatostatin derivative. In this case, the
pharmaceutical preparation comprising tolvaptan or a prodrug
thereof may be, for example, an orally administered drug (an oral
preparation), an intramuscularly administered drug (a
sustained-release preparation), or an intravenously administered
drug (a sustained-release preparation); the pharmaceutical
preparation is preferably an oral preparation. The pharmaceutical
preparation comprising a somatostatin derivative may be, for
example, a subcutaneously administered drug (a subcutaneous
injection), an intramuscularly administered drug (a
sustained-release preparation), or an orally administered drug (an
oral preparation), and is preferably a subcutaneously administered
drug.
[0097] Examples of the combination of concomitants include, but are
not limited to, a combination of an orally administered drug
comprising tolvaptan or a prodrug thereof and a subcutaneously
administered drug comprising a somatostatin derivative, and a
combination of one drug comprising tolvaptan or a prodrug thereof
and another drug comprising a somatostatin derivative, both being
subcutaneously administered drugs (subcutaneous injections).
[0098] The dose of the combination drug of the present invention is
suitably selected according to the dosage regimen, the patient's
age and sex, the severity of the disease, and other conditions.
[0099] The dosage regimen of the pharmaceutical preparation
comprising tolvaptan or a prodrug thereof is usually such that
tolvaptan or a prodrug thereof is administered in an amount of
about 0.001 to 300 mg, preferably 0.001 to 100 mg, per kg (body
weight) per day in one or more administrations.
[0100] Even when tolvaptan or a prodrug thereof is administered in
a low dose that would be ineffective if used alone, a combination
thereof with a somatostatin derivative can provide excellent
therapeutic effects on polycystic kidney disease. The dosage
regimen of the pharmaceutical preparation comprising tolvaptan or a
prodrug thereof when used in combination with a somatostatin
derivative is such that tolvaptan or a prodrug thereof is
administered in an amount of about 0.001 to 50 mg, and preferably
0.001 to 30 mg, per kg (body weight) per day in one or more
administrations.
[0101] The dosage regimen of the preparation comprising a
somatostatin derivative is usually such that the somatostatin
derivative is administered in an amount of about 0.001 to 10 mg,
preferably 0.001 to 1 mg, per kg (body weight) per day in one or
more administrations.
[0102] The pharmaceutical preparation comprising tolvaptan or a
prodrug thereof with the pharmaceutical preparation comprising a
somatostatin derivative can be administered to a human (in
particular, a patient) simultaneously or with a delay between
administrations.
[0103] The present invention includes use of a combination of
tolvaptan or a prodrug thereof with a somatostatin derivative in
the manufacture of a drug for preventing and/or treating polycystic
kidney disease.
[0104] The present invention includes a combination drug of
tolvaptan or a prodrug thereof and a somatostatin derivative for
use in the prevention and/or treatment of polycystic kidney
disease.
[0105] The present invention includes a method for treating
polycystic kidney disease, comprising administering a combination
of tolvaptan or a prodrug thereof with a somatostatin derivative to
a polycystic kidney disease patient. Preferable dosage forms are
such that tolvaptan is administered orally and a somatostatin
derivative is administered subcutaneously or intramuscularly.
[0106] The present invention includes a kit for preventing and/or
treating polycystic kidney disease comprising an orally
administered drug comprising tolvaptan or a prodrug thereof and an
injectable preparation (in particular, a subcutaneously
administered drug or an intramuscularly administered drug)
comprising a somatostatin derivative. Examples of the kit include a
kit comprising a container containing an orally administered drug
comprising tolvaptan or a prodrug thereof and a container
containing a subcutaneously administered drug or an intramuscularly
administered drug comprising a somatostatin derivative.
[0107] The entire contents and disclosures of each patent and
reference disclosed herein are incorporated by reference.
EXAMPLES
[0108] The present invention will now be illustrated with the
following examples. However, the invention is not limited thereto
or thereby.
Example 1
[0109] Individual or combined effects of tolvaptan, which is a
vasopressin receptor antagonist, and octreotide, which is a
somatostatin analogue, against polycystic kidney disease were
evaluated using pcy mice, which are PKD model animals.
[0110] The aforementioned pcy mice are adult polycystic kidney
disease model mice, and the mode of inheritance is autosomal
recessive. In DBA/2FG-pcy mice generated by introducing the pcy
gene into DBA/2 mice, cysts were observed with the naked eye from
the fourth week, and the kidney volume increased over time until
the 30th week. It has been reported that compared to wild-type
mice, pcy mice have increased renal cAMP levels and elevated renal
mRNA levels of aquaporin-2 and vasopressin V2 receptor (V2R). For
details, see Non-patent Literature (NPL) 1.
[0111] Based on the body weight at 4 weeks of age and the renal
volume measured by MRI, the pcy mice (male) were divided into the
following four groups (each group: 9 mice): [0112] (1) a control
group; [0113] (2) a group receiving a feed containing 0.03%
tolvaptan; [0114] (3) a group receiving octreotide (300
mg/kg.times.2/day sc); and [0115] (4) a group receiving a feed
containing 0.03% tolvaptan, and octreotide (300
.mu.g/kg.times.2/day sc). As normal control mice, DBA/2JJcl mice (5
mice) were used. A 0.03% tolvaptan-containing MF feed was given to
the groups receiving tolvaptan. A MF feed not containing tolvaptan
was given to the other groups, i.e., the control group and the
group receiving octreotide alone. Sandostatin subcutaneous
injection (100 .mu.g/ml) was diluted with physiological saline and
subcutaneously injected in an amount of 300 .mu.g/kg/10 ml to the
group receiving octreotide twice a day, morning and evening.
[0116] The drug treatment was started from 5 weeks of age, and
continued until 15 weeks of age. Urine was collected from each
mouse at 14 weeks of age using metabolic cages for 19 hours, and
urine volume and urinary albumin excretion were measured.
[0117] The DEA control mice and pcy mice were sacrificed under
isoflurane anesthesia at 15 weeks of age to collect their blood,
and right and left kidneys. Plasma parameters were measured from
the obtained blood, and the weight of right and left kidneys was
measured.
[0118] Table 1 shows the weight of the kidneys (% body weight)
during autopsy. At 15 weeks of age, marked renal hypertrophy and
cysts were observed in pcy control mice, compared to normal DBA
mice. The kidney weight was increased 5.2-fold. Compared to the pcy
control group, the group receiving 0.03% tolvaptan-containing feed
and the group subcutaneously receiving octreotide did not exhibit
significant kidney weight suppressive effects when either tolvaptan
or octreotide was administered alone. In contrast, a significant
kidney weight suppressive effect was observed in the group
receiving both tolvaptan and octreotide (p<0.01), compared to
the pcy control. The group receiving both tolvaptan and octreotide
exhibited a significantly high kidney weight suppressive effect
(p<0.05), compared to the groups receiving either tolvaptan or
octreotide alone.
TABLE-US-00001 TABLE 1 Kidney weight of (15-week-old) pcy mice
(body weight adjustment: %) Assay results Comparison Comparison
with the group Kidney weight with the receiving both Number (% body
weight) control of tolvaptan Group of mice of mice Mean .+-. SE
group and octreotide 1 Normal DBA 5 1.53 .+-. 0.04 -- -- 2 Pcy
control 9 8.02 .+-. 0.66 -- -- 3 Pcy receiving 0.03% tolvaptan- 9
7.28 .+-. 0.84 NS p < 0.05 containing feed alone 4 Pcy receiving
octreotide alone 9 6.68 .+-. 0.65 NS p < 0.05 (300 .mu.g/kg
.times. 2/day sc) 5 Pcy receiving both 0.03% 9 4.87 .+-. 0.36 p
< 0.01 -- tolvaptan-containing feed and octreotide (300 .mu.g/kg
.times. 2/day sc) Each value indicates the average value .+-. SEM.
For comparison with the control group, Dunnett's test (both sides)
was used. For comparison of the group receiving both of tolvaptan
and octreotide with the groups receiving either one of tolvaptan
and octreotide, the closed testing procedure was used. "NS"
indicates non-significant.
[0119] The above results show that a combination of tolvaptan with
octreotide can synergistically suppress cystic kidney enlargement
and improve kidney functions.
* * * * *