U.S. patent application number 10/204555 was filed with the patent office on 2003-09-04 for compositions for preventing and treating digestive organs diseases.
Invention is credited to Araki, Hiromasa, Kakehi, Kazuaki, Kawabata, Atsufumi, Kawai, Kenzo, Kuroda, Ryotaro, Nishikawa, Hiroyuki, Nishimura, Sachiyo, Tanaka, Shuichi.
Application Number | 20030166553 10/204555 |
Document ID | / |
Family ID | 18569755 |
Filed Date | 2003-09-04 |
United States Patent
Application |
20030166553 |
Kind Code |
A1 |
Araki, Hiromasa ; et
al. |
September 4, 2003 |
Compositions for preventing and treating digestive organs
diseases
Abstract
The present invention provides a composition for safely and
effectively preventing and treating digestive organs diseases,
particularly, gastric ulcer, duodenal ulcer, gastritis, diarrhea,
enteritis and the like. There is also provided a composition having
a novel mechanism of action in order to solve the problems which
was difficult to be solved by the side effect previously known
mechanisms of action. More particularly, there is provided a
pharmaceutical composition containing an ingredient which activates
PAR-2 as an essential ingredient, which is useful for inhibiting
gastric acid secretion, promoting digestive tract mucus secretion,
protecting digestive tract mucosa, repairing tissue of digestive
organs, and preventing and treating digestive organs diseases.
Inventors: |
Araki, Hiromasa;
(Yamatokoriyama-shi, JP) ; Kawabata, Atsufumi;
(Yamatotakada-shi, JP) ; Kuroda, Ryotaro;
(Osaka-shi, JP) ; Kakehi, Kazuaki; (Nara-shi,
JP) ; Tanaka, Shuichi; (Sennan-gun, JP) ;
Kawai, Kenzo; (Matsubara-shi, JP) ; Nishimura,
Sachiyo; (Sakurai-shi, JP) ; Nishikawa, Hiroyuki;
(Kashiba-shi, JP) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.
624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Family ID: |
18569755 |
Appl. No.: |
10/204555 |
Filed: |
August 22, 2002 |
PCT Filed: |
February 20, 2001 |
PCT NO: |
PCT/JP01/01188 |
Current U.S.
Class: |
514/13.2 ;
514/12.3; 514/12.8; 514/20.3 |
Current CPC
Class: |
A61K 38/08 20130101;
A61K 38/06 20130101; A61K 38/482 20130101; A61P 1/12 20180101; A61P
1/04 20180101; A61P 1/00 20180101; A61K 38/4826 20130101; A61K
38/06 20130101; A61K 2300/00 20130101; A61K 38/4826 20130101; A61K
2300/00 20130101; A61K 38/482 20130101; A61K 2300/00 20130101; A61K
38/08 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/12 ;
514/17 |
International
Class: |
A61K 038/17; A61K
038/08 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 24, 2000 |
JP |
2000-47515 |
Claims
What is claimed is:
1. A composition for inhibiting gastric acid secretion, comprising
an ingredient which activates PAR-2.
2. A composition for promoting gastrointestinal mucus secretion,
comprising an ingredient which activates PAR-2.
3. A composition for protecting gastrointestinal mucosa, comprising
an ingredient which activates PAR-2.
4. A composition for preventing or treating digestive organs
diseases, comprising an ingredient which activates PAR-2.
5. The composition according to claim 4, wherein the digestive
organs disease is the disease selected from gastric ulcer, duodenal
ulcer, gastritis, diarrhea, and enteritis.
6. The composition according to any one of claims 1-5, wherein the
ingredient is a peptide.
7. The composition according to claim 6, wherein the peptide
comprises at least one sequence selected from the group consisting
of Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ ID NO: 1) and
trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-ornithine-NH.sub.2 (SEQ ID NO:
2).
8. The composition according to any one of claims 1-5, wherein the
ingredient is a protein.
9. The composition according to claim 8, wherein the protein is at
least one selected from trypsin and tryptase.
10. The composition according to any one of claims 1-9, which is
combined with an inhibitory substance which inhibits an activity of
substance for inactivating or degrading the ingredient.
11. The composition according to claim 10, which is used together
with an inhibitory substance which inhibits an activity of
substance for inactivating or degrading the ingredient.
12. The composition according to claim 10, which is incorporated
with an inhibitory substance which inhibits an activity of
substance for inactivating or degrading the ingredient.
13. The composition according to any one of claims 10-12, wherein
the inhibitory substance is a peptidase inhibitor.
14. The composition according to claim 13, wherein the peptidase
inhibitor is amastatin.
15. The composition according to any one of claims 1-14, which is
formulated into a DDS preparation.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compositions for preventing
and treating digestive organs diseases, especially, compositions
for preventing and/or treating gastric ulcer, duodenal ulcer,
gastritis, diarrhea, enteritis and the like.
BACKGROUND OF THE INVENTION
[0002] Peptic ulcer such as gastric ulcer, duodenal ulcer and the
like are resulted from the disruption of a balance between
aggressive factors and protective factors. Example of
disruption-inducing factors include drugs (e.g., non-steroidal
anti-inflammatory agents, adrenocortical hormone agents,
antibiotics, anti-cancer agents, oral hypoglycemic agents), stress,
alcohols, corrosive drugs, cirrhosis, anisakid spp., eating habits
and the like. At present, aggressive factor inhibitors, protective
factor enhancers, and combinations thereof are clinically used.
[0003] As the aggressive factor inhibitors, there are clinically
used antacids (e.g., sodium bicarbonate and aluminum hydroxide gel,
magnesium oxide etc.), anticholinergics (e.g., atropine sulfate,
pirenzepine hydrochloride etc.), H2-receptor antagonists (e.g.,
cimetidine, ranitidine, famotidine, nizatidine, roxatidine etc.),
proton pump inhibitors (e.g., omepurazor, ransoprazol, ransoprazol
sodium etc.), anti-gastrin drugs (e.g., proglumide, secretin,
urogastorone), and anti-pepsin drugs (sucrose sulfate ester,
sucralfate etc.) and the like.
[0004] As the protective factor enhancers, there are clinically
used mucosal protective drugs (e.g., sucralfate, rebamipide,
teprenone etc.), mucosal covering drugs (e.g., sodium arginate,
azunol preparation etc.), tissue repair accelerating drugs (e.g.,
aceglutamide aluminum, aldioxa, gefalnate etc.), mucus production
accelerating drugs (e.g., proglumide, teprenone, secretin, aldioxa
etc.), mucosal microcirculation improving drugs (e.g., cetraxate
hydrochloride, benexate, sulpirid etc.), prostaglandin synthesis
accelerating drugs (e.g., sofalcone) and prostaglandin preparations
(e.g., ornoprostil, misoprostol, enprostil etc.) and the like. For
chronic gastritis, digestive tract function improving drugs (e.g.,
cisapride, aclatonium napadisilate, bethanechol, domperidone,
metoclopramide, trimebutine maleate) are also used.
[0005] Aggressive factor inhibitors, H2-receptor antagonists,
proton pump inhibitors and the like are widely used because of
having a potent gastric acid secretion-inhibiting activity and a
prominent therapeutic effect. However, it has been revealed that
there are high frequently a rebound of gastric acid secretion, and
recurrence or exacerbation of ulcer when a drug administration is
stopped even after completely cured once. Further, there were
problems that there are ulcers which are not completely cured by a
H2-receptor antagonist, and that hyperplasia of an
enterochromaffin-like cell, hypergastrinemia, appearance of gastric
carcinoid and the like are reported depending on use of a proton
pump inhibitor and, thus, its dose is limited. While the protective
factor enhancers have more mild actions as compared with the above
aggressive factor inhibitors, their therapeutic effects were
subsidiary. Therefore, patients having digestive organs disease and
physicians have desired development of an aggressive factor
inhibitor or a protective factor enhancer, which is neither a
H2-receptor antagonist nor a proton pump inhibitor and can be
safely and effectively used through other mechanism of action.
[0006] Meanwhile, it is known that PAR (protease-activated
receptor) belongs to a seven-transmembrane type G protein coupling
receptor, and is a receptor activated by a protease (Hollenberg, M.
D., Trends Pharmacol. Sci., 17, 3-6, 1996; Hollenberg, M. D.,
Trends Pharmacol. Sci., 20, 271-273, 1999). PAR is cleaved by a
protease at a specific N-terminal site of an extracellular domain,
to expose a new N-terminus. It is believed that the newly exposed
N-terminus becomes a chain ligand and is bound to its own
activation site, whereby, activation of receptor is caused
(Hollenberg, M. D., Trends Pharmacol. Sci., 17, 3-6, 1996;
Hollenberg, M. D., Trends Pharmacol. Sci., 20, 271-273, 1999; Vu,
T. K. et al., Cell, 64, 1057-68, 1991).
[0007] It is reported that subtypes of PAR-1, PAR-2, PAR-3, and
PAR-4 exist in PAR, and that their functions differ from each
another. It is found that PAR-1, PAR-3, and PAR-4 are activated by
thrombin (Vu, T. K. et al., Cell, 64, 1057-1063, 1991; Hollenberg,
M. D., Trends Pharmacol. Sci., 17, 3-6, 1996; Ishihara, H. et al.,
Nature, 386, 502-6, 1997; Kahn, M. L. et al., Nature, 394, 690-4,
1998; Xu, W. F. et al., Proc. Natl. Acad. Sci. USA, 95, 6642-6,
1998), and PAR-2 is activated by trypsin (Nystedt, S. et al., Proc.
Natl. Acad. Sci. USA, 91, 9208-12, 1994; Molino, M. et al., J.
Biol. Chem., 272, 6011-7, 1997) and tryptase (Molino, M. et al., J.
Biol. Chem., 272, 6011-7, 1997; Fox, M. T. et al., FEBS Lett, 417,
267-9, 1997).
[0008] It is also known that there is a cleavage site on an amino
acid sequence of the PAR-1 (Vu, T. K. et al., Cell, 64, 1057-1063,
1991), PAR-2 (Nystedt, S. et al., Proc. Natl. Acad. Sci. USA, 91,
9208-12, 1994), RAR-3 (Ishihara, H. et al., Nature, 386, 502-6,
1997) and PAR-4 (Kahn, M. L. et al., Nature, 394, 690-4, 1998; Xu,
W. F. et al., Proc. Natl. Acad. Sci. USA, 95, 6642-6, 1998), and
with respect to PAR-1, PAR-2 and PAR-4, the receptor is activated
by exogenously adding a synthetic peptide consisting of five or six
amino acids synthesized on the basis of an active amino acid
sequence of a cleavage site (Vu, T. K. et al., Cell, 64, 1057-68,
1991; Nystedt, S. et al., Proc. Natl. Acad. Sci. USA, 91, 9208-12,
1994; Ishihara, H. et al., Nature, 386, 502-6, 1997; Kahn, M. L. et
al., Nature, 394, 690-4, 1998; Xu, W. F. et al., Proc. Natl. Acad.
Sci. USA, 95, 6642-6, 1998; Dery, O. et al., Am. J. Physiol., 274,
C1429-52, 1998).
[0009] As one of the intracellular signals mediated by PAR-2,
activation of inositol 1,4,5-triphosphate (IP3) and protein kinase
C system are known (Hollenberg, M. D., Trends Pharmacol. Sci., 20,
271-273, 1999; Dery, O. et al., Am. J. Physiol., 274, C1429-52,
1998; Zheng, X. L. et al., J Pharmacol Exp Ther, 285, 325-34,
1998).
[0010] With respect to PAR-2, it is reported that there are
inflammatory responses (Cirono, G. et al., J. Exp. Med., 183,
821-827, 1996; Kawabata, A et al., Br. J. Pharmacol., 125, 419-422,
1998), constricting and relaxing actions in trachea (Saifeddine, M.
et al., Br. J. Pharmacol., 118, 521-531, 1996; Moffatt, J. D. et
al., Br. J. Pharmacol., 125, 591-594, 1998; Cocks, T. M. et al.,
Nature, 398, 156-160, 1999; Hollenberg, M. D. et al., Can. J.
Physiol. Pharmacol., 75, 832-884, 1997), and that PAR-2 is
expressed in prostate gland, small intestine, colon, liver, kidney,
and pancreas (Stephan, K. B. et al., Biochem. J., 341, 1009-1016,
1996).
[0011] However, there have not been reported to date on digestive
organ system, such as a gastric acid secretion inhibiting action, a
mucus secretion promoting action and a mucosal protecting action of
PAR-2.
OBJECTS OF THE INVENTION
[0012] The present invention was done in view of the aforementioned
prior art, and an object of the invention is to provide safe and
effective compositions for a preventing and treating digestive
organs diseases, especially, compositions for preventing and/or
treating gastric ulcer, duodenum ulcer, gastritis, diarrhea,
enteritis and the like.
[0013] Another object is to provide compositions described above
having a novel mechanism of action in order to solve the problem
which was difficult to be solved by the side effect previously
known mechanisms of action.
SUMMARY OF THE INVENTION
[0014] The present inventors studied in order to develop a
preferred drug in a composition for treating and/or preventing
digestive organs disease, especially gastric ulcer, duodenum ulcer,
gastritis, diarrhea, enteritis and the like, and intensively
researched for finding out new mechanisms of action. Consequently,
we first found out that an ingredient which activates PAR-2
(agonist) has an action on digestive system, that is, the
ingredient inhibits gastric acid, promotes digestive tract mucus
secretion, and has mucosal protective action, which resulted in
completion of the present invention.
[0015] Thus, the present invention provides:
[0016] (1) a composition for inhibiting gastric acid secretion,
comprising an ingredient which activates PAR-2,
[0017] (2) a composition for promoting gastrointestinal mucus
secretion, comprising an ingredient which activates PAR-2,
[0018] (3) a composition for protecting gastrointestinal mucosa,
comprising an ingredient which activates PAR-2,
[0019] (4) a composition for preventing or treating digestive
organs diseases, comprising an ingredient which activates
PAR-2,
[0020] (5) the composition according to (4), wherein the digestive
organs disease is the disease selected from gastric ulcer, duodenal
ulcer, gastritis, diarrhea, and enteritis,
[0021] (6) the composition according to any one of (1)-(5), wherein
the ingredient is a peptide,
[0022] (7) the composition according to (6), wherein the peptide
comprises at least one sequence selected from the group consisting
of Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ ID NO: 1) and
trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-ornithine-NH.sub.2 (SEQ ID NO:
2),
[0023] (8) the composition according to any one of (1)-(5), wherein
the ingredient is a protein,
[0024] (9) the composition according to (8), wherein the protein is
at least one selected from trypsin and tryptase,
[0025] (10) the composition according to any one of (1)-(9), which
is combined with an inhibitory substance which inhibits an activity
of substance for inactivating or degrading the ingredient,
[0026] (11) the composition according to (10), which is used
together with an inhibitory substance which inhibits an activity of
substance for inactivating or degrading the ingredient,
[0027] (12) the composition according to (10), which is
incorporated with an inhibitory substance which inhibits an
activity of substance for inactivating or degrading the
ingredient,
[0028] (13) the composition according to any one of (10)-(12),
wherein the inhibitory substance is a peptidase inhibitor,
[0029] (14) the composition according to (13), wherein the
peptidase inhibitor is amastatin, and
[0030] (15) the composition according to any one of (1)-(14), which
is formulated into a DDS preparation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 is a view showing the gastric acid secretion
inhibiting effect of a PAR-2 agonist peptide on acceleration of
carbachol-inducing gastric acid secretion in vivo. **P<0.01 vs.
V (Tukey's test).
[0032] FIG. 2 is a view showing the effects of PAR-2 agonists
peptide on secretion of mucin from gastric mucosa cells in vivo.
**P<0.01 vs. V (Tukey's test).
[0033] FIG. 3 is a view showing the effect of a PAR-2 agonist
peptide on the lesion of gastric mucosa by ethanol in vivo.
**P<0.0l vs. V (Tukey's test).
[0034] FIG. 4 is a view showing the effect of a PAR-2 agonist
peptide on the lesion of gastric mucosa by hydrochloride-ethanol in
vivo. **P<0.0l vs. V (Tukey's test).
DETAILD DESCRIPTION OF THE INVENTION
[0035] An "ingredient which activates PAR-2" refers to any
naturally occurring or artificially synthesized substance which has
the ability to activate PAR-2 and includes a peptide, a protein,
other compounds and the like. More specifically, examples of the
ingredient which activates PAR-2 include trypsin and tryptase which
are natural PAR-2 activating proteins, the peptide
Ser-Phe-Leu-Leu-Arg-NH.sub.2 (SEQ ID NO: 3) (hereinafter, referred
to as "SFp-NH.sub.2") which is synthesized based on the previously
reported amino acid sequence of human PAR-1 (Vu, T. K. et al.,
Cell, 64(6), 1057-1068, 1991), which is known to have an agonist
activity on human PAR-1 (Hollenberg, M. D., Molec. Pharmacol., 43,
921-930, 1993; Hollenberg, M. D., Trends Pharmacol. Sci., 17, 3-6,
1996) and have a week agonist activity on PAR-2 (Kawabata, A. et
al., J. Pharmacol. Exp. Ther., 288, 358-70, 1999), the peptide
Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ ID NO: 1)(hereinafter,
referred to as "SLp-NH.sub.2") (Hollenberg, M. D., Trends
Pharmacol. Sci., 17, 3-6, 1996; Nystedt, S. et al., Proc. Natl.
Acad. Sci. USA, 91, 9208-12, 1994) which is synthesized based on
amino acid sequence of rat PAR-2 (Saifeddine, M. et al., Br. J.
Pharmacol., 118(3), 521-530, 1996), the peptide
Ser-Leu-Ile-Gly-Arg-Leu-OH (SEQ ID NO: 4) (hereinafter, referred to
as "SLp-OH") in which a C-terminus of SLp-HN2 is not amidated, the
peptide trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-- ornithine-NH.sub.2
(SEQ ID NO: 2) (hereinafter, referred to as "tcLp-NH.sub.2")
(Hollenberg, M. D. et al., Can J Physiol Pharmacol, 75, 832-41,
1997) which is reported to specifically activate PAR-2, and the
like. Furthermore, an antibody to PAR-2 or its fragment may also
serve as a protein or a peptide which activates PAR-2
specifically.
[0036] The ingredient which activates PAR-2 may be obtained by
screening various substances for the ability to activate PAR-2,
according to any of the known methods. For example, the substance
which binds to PAR-2 may be screened by directly detecting the
interaction between PAR-2 and a test substance using labeling with
a radioisotopic element, surface plasmon resonance or the like. A
substance which induces signal transmission via PAR-2 may be
screened using as an index of the biological activity caused by
activation of PAR-2 in the cell or tissue expressing PAR-2.
Further, the substance which has the gastric acid secretion
inhibiting activity, the mucus promoting activity or the mucosa
protecting activity, can be screened using a method for measuring
an amount of gastric acid secretion, an amount of mucus secretion
or the mucosa protecting activity shown in Examples. An assay for
activation of PAR-2 is described in, for example, Hollenberg, M.
D., Can. J. Physiol. Pharmacol., 75, 832-841, 1997 and Kawabata,
A., J. Pharmacol. Exp. Ther., 288, 358-370, 1999. A method for
screening a substance (i.e. agonist) which binds to and acts on a
receptor is well-known in the art (see, for example, Hollenberg, M.
D., Trends Pharmacol. Sci., 20, 271-273, 1999; Dery, O., Am. J.
Physiol., 274, C1429-C1452, 1998; Kawabata, A., J. Pharmacol. Exp.
Ther., 288, 358-370, 1990).
[0037] As used herein, the term "peptide" refers to an oligopeptide
and a relatively short polypeptide. The peptide contains, for
example, 2-40 amino acid residues, preferably 3-20 amino acid
residues, and more preferably, 5-15 amino acid residues. The
peptide may be naturally occurring or may be chemically
synthesized. The peptide may be synthesized according to the known
method described in, for example, Carpino, L. A. et al., J. Org.
Chem., 37,3404-3409, 1972. Alternatively, the peptide may be
produced using the recombinant DNA technology. Furthermore, the
peptide may contain modified or non-natural amino acid
residues.
[0038] AS used herein, the term "protein" refers to a longer
polypeptide as compared with the peptide. The protein may be
purified from a natural source, or may be produced by culturing a
recombinant host cell containing a DNA encoding this protein. The
protein may be chemically synthesized as well as the peptide. The
protein may contain modified or non-natural amino acid
residues.
[0039] Thus, since the ingredient which activates PAR-2 inhibits
the gastric acid secretion, promotes the gastric mucus secretion,
and also has the mucosa protecting activity, a composition
containing the ingredient which activates PAR-2 of the invention is
useful as a composition for inhibiting the gastric acid secretion,
a composition for promoting the digestive mocus secretion, a
composition for repairing a gastrointestinal tissue and a
composition for protecting a gastrointestinal mucosa, is useful as
a composition for preventing and treating digestive organs disease,
and especially useful for preventing and/or treating gastric ulcer,
duodenal ulcer, gastritis, diarrhea, enteritis and the like.
[0040] When used as a preventive agent or a therapeutic agent, the
composition of the invention may be used as it is or by various
treatments such as on dilution with water and the like, and may be
used by incorporating into a pharmaceutical, a quasi drug and the
like. In this case, although an amount of the ingredient which
activates PAR-2 to be incorporated is suitably selected depending
on a product, the amount in the case of a systemic preparation
usually may be 0.001-50% by weight, especially, 0.01-10% by weight.
The sufficient activity in the prevention or treatment may not be
shown when the amount is less than 0.001%, and the properties such
as stability, flavoring and the like may be deteriorated when the
amount exceeds 50%.
[0041] The ingredient which activates PAR-2 contained in the
composition of the invention may be contained in a preparation as a
pharmaceutically acceptable salt. Examples of the pharmaceutically
acceptable salt include salts with a base such as an inorganic
base, an organic base and the like, and an acid addition salt such
as an inorganic acid, an organic acid, a basic or acidic amino acid
and the like. Examples of the inorganic base contain an alkali
metal such as sodium, potassium and the like, an alkaline-earth
metal such as calcium, magnesium and the like, aluminum, ammonium,
and the like. The organic base contains, for example, a primary
amine such as ethanolamine and the like, a secondary amine such as
diethylamine, diethanolamine, dicyclohexylamine,
N,N'-dibenzylethylene-diamine and the like, a tertiary amine such
as trimethylamine, triethylamine, pyridine, picoline,
triethanolamine, and the like. Examples of the inorganic acid
include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid, phosphoric acid and the like. Examples of the organic acid
include formic acid, acetic acid, lactic acid, trifluoroacetic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
benzoic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid and the like. Examples of the basic amino
acid include arginine, lysine, ornithine and the like. Examples of
the acidic amino acid include aspartic acid, glutamic acid and the
like.
[0042] When a peptide or a protein is used as the ingredient which
activates PAR-2, since the peptide or the protein is degraded by
peptidase present in the living body, the durability of the
activity of activating PAR-2 can be enhanced by combination by
using together with or incorporating therein a drug such as
amastatin which is a peptidase inhibitor. When the aforementioned
ingredient is not a peptide, those skilled in the art can suitably
identify the substance for inactivating or degrading the
ingredient, select an inhibitory substance which inhibits a
substance for inactivating or degrading the ingredient, and use or
incorporate therein the substance.
[0043] As a method of administering the composition of the present
invention, in addition to oral and intravenous administration,
transmucosal, transcutaneous, intramuscular, subcutaneous,
intrarectal administration or the like can be suitably selected,
and the composition can be used as various preparations depending
on the method of administration.
[0044] Respective preparations will be described below. The
preparation types used in the invention are not limited to them,
but the composition may be used as various preparations usually
used in the field of pharmaceutical preparation.
[0045] When used as a preventive or therapeutic drug for digestive
organs disease, a dose of oral administration of the ingredient
which activates PAR-2 is preferably in a range of 3-300 mg/kg, more
preferably 10-100 mg/kg. When administered systemically, in
particular, by intravenous administration, a dose varies depending
upon age, sex, body type and the like, the preparation should be
administered so that an effective blood concentration is preferably
in a range of 2-200 .mu.g/mL, more preferably 5-100 .mu.g/mL.
[0046] As a dosage form in the case of oral administration, there
are powders, granules, capsules, pills, tablets, elixirs,
suspensions, emulsions, syrups and the like, and these dosage forms
may be selected suitably. Moreover, these preparations may be
subjected to modification such as sustained-release, stabilization,
easy disintegration, poor disintegration, enteric coating, easy
absorption and the like. Moreover, as a dosage form in the case of
local administration in oral cavity, there are chewable
preparations, sublingual preparations, buccal preparations,
troches, ointments, patchs, solutions and the like, and these
preparations may be selected suitably. These preparations may be
also subjected to modification such as sustained-release,
stabilization, easy disintegration, poor disintegration, enteric
coating, easy absorption and the like.
[0047] For each dosage form described above, the technology of the
known drug delivery system (DDS) may be adapted. As used herein,
the "DDS preparation" refers to a preparation made in an optimal
form of preparation, such as a sustained-release preparation, a
preparation for local application (troches, buccal preparations,
sublingual preparations etc.), a controlled release preparation, an
enteric coated preparation, a non enteric coated preparation and
the like after taking into consideration a route of administration,
bioavailability, side effects and the like.
[0048] The constituent elements of DDS consist fundamentally of a
drug, a drug-release module, a coating and a therapeutic program
and, for each of constituent elements, especially, a drug with
short half-life which reduces the blood concentration rapidly when
release is stopped is preferable, a coating which does not react
with the organism tissue at an administration site is preferable,
and further a therapeutic program which maintains the optimal drug
concentration during a set period is preferable. The drug-release
module has fundamentally a drug reservoir, a release controlling
part, an energy source, and a releasing pore or surface. All of
these fundamental constituent elements are not necessary to exists
together, and an optimal preparation may be selected by suitably
adding or deleting some elements.
[0049] There are polymers, cyclodextrin derivatives, lecithin and
the like as a material which may be used in DDS. Examples of the
polymers include insoluble polymers (silicone, ethylene-vinyl
acetate copolymer, ethylene-vinyl alcohol copolymer, ethyl
cellulose, cellulose acetate etc.), water-soluble polymers and
hydroxyl gel forming polymers (polyacrylamide, cross-linked
polyhydroxyethyl methacrylate substance, cross-linked polyacrylate,
polyvinyl alcohol, polyethylene oxide, a water-soluble cellulose
derivative, a cross-linked poloxamer, chitin, chitosan etc.),
slowly-soluble polymers (ethyl cellulose, a partial ester of methyl
vinyl ether-maleic anhydride copolymer etc.), non-enteric coating
polymers (hydroxypropylmethyl cellulose and hydroxypropyl
cellulose, sodium carmellose, macrogol, polyvinyl pyrrolidone,
dimethylaminoethyl methacrylate-methyl methacrylate copolymer
etc.), enteric polymers (hydroxypropylmethyl cellulose phthalate,
cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate
succinate, carboxymethylethyl cellulose, acrylate polymer etc.),
biodegradable polymers (thermocoagulating or cross-linked albumin,
cross-linked gelatin, collagen, fibrin, polycyanoacrylate,
polyglycolic acid, polylactic acid, poly(.beta.-hydroxyacetic
acid), polycaprolactone etc.), and the polymers can be selected
suitably depending on a dosage form.
[0050] Particularly, silicone, ethylene-vinyl acetate coplymer,
ethylene-vinyl alcohol copolymer, a partial ester of methyl vinyl
ether-maleic anhydride may be used in a controlled-release of drug,
cellulose acetate may be used as a material for an osmotic pressure
pump, ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose and methyl cellulose may be used as a membrane material
for a controlled release preparation, and cross-linked polyacrylate
may be used as an adhesive agent for oral or ophthalmic mucosa.
[0051] Moreover, preparations may be produced by adding an
additive, such as a solvent, a vehicle, a coating agent, a base, a
binder, a lubricant, a disintegrant, a solution adjuvant, a
suspending agent, a viscosity-increasing agent, an emulsifying
agent, a stabilizer, a buffer, a tonicity agent, a soothing agent,
a preservative, a flavoring agent, an aroma, a colorant and the
like, depending on their dosage forms (the known preparation such
as oral preparations, injections, suppositories etc.)
[0052] The following embodiments for each of these additives are
exemplified, being not particularly limited.
[0053] Solvents: purified water, water for injection, physiological
saline, peanut oil, ethanol, and glycerin;
[0054] Vehicles: starch, lactose, glucose, sucrose,
microcrystalline cellulose, calcium sulfate, calcium carbonate,
talc, titanium oxide, trehalose, and xylitol;
[0055] Coating agents: sucrose, gelatin, cellulose acetate
phthalate, and the aforementioned polymers;
[0056] Bases: vaseline, vegetable oil, macrogol, oil in water type
emulsion base, water in oil type emulsion base,
[0057] Binders: starch and derivatives thereof, cellulose and
derivatives thereof, naturally-occurring high molecular compounds
such as gelatin, sodium alginate, tragacanth, acacia and the like,
synthetic high molecular compounds such as polyvinyl pyrrolidone,
dextrin, and hydroxypropyl starch;
[0058] Lubricants: stearic acid and salts thereof, talc, wax, wheat
starch, macrogol, hydrogenated vegetable oil, sucrose fatty acid
ester, and polyethylene glycol;
[0059] Disintegrants: starch and derivatives thereof, gelatin,
gelatin powder, sodium bicarbonate, cellulose and derivatives
thereof, calcium carmellose, hydroxypropyl starch, carboxymethyl
cellulose and salts and cross-linked materials thereof, and
low-substituted types of hydroxypropyl cellulose;
[0060] Solution adjuvants: cyclodextrin, ethanol, propylene glycol,
and polyethylene glycol;
[0061] Suspending agents: acacia, tragacanth, sodium alginate,
aluminium monostearate, citric acid, and various surfactants;
[0062] Viscosity-increasing agents: sodium carmellose, polyvinyl
pyrrolidone, methyl cellulose, hydroxypropylmethyl cellulose,
polyvinyl alcohol, tragacanth, acacia, and sodium alginate;
[0063] Emulsifying agents: acacia, cholesterol, tragacanth,
methylcellulose, various surfactants, lecithin,
[0064] Stabilizers: sodium hydrogensulfite, ascorbic acid,
tocopherol, chelating agent, inert gas, and reducing substance;
[0065] Buffers: sodium hydrogenphosphate, sodium acetate, and boric
acid;
[0066] Tonicity agents: sodium chloride, and glucose;
[0067] Soothing agents: procaine hydrochloride, lidocaine, benzyl
alcohol;
[0068] Preservatives: benzoic acid and salts thereof,
para-oxybenzoic acid esters, chlorobutanol, invert soap, benzyl
alcohol, phenol, and thimerosal;
[0069] Flavoring agents: sucrose, saccharin, glycyrrhiza extract,
sorbitol, xylitol, and glycerin;
[0070] Aromas: orange peel tincture and rose oil; and
[0071] Colorants: water-soluble food pigment, and lake pigment.
[0072] As described above, effects such as the durability the
effective blood concentration of a drug and improvement in
bioavailability can be expected by formulating a pharmaceutical
into a DDS preparation such as sustained release preparation,
enteric-coated preparation, controlled-release preparation or the
like. However, an ingredient which activates PAR-2 is inactivated
or degraded in a living body, consequently, the desired effect may
be decreased or eliminated. For example, it is known that, when the
ingredient which activates PAR-2 is a peptide, many of such the
peptides will be degraded by aminopeptidase in the living body
(Godin, D. et al., Eur. J. Pharmacol., 253, 225-30, 1994).
Therefore, the effect of the ingredient may be further sustained by
using an inhibitory substance which inhibits an activity of
substance for inactivating or degrading the ingredient which
activates PAR-2 (e.g., an inhibitory substance for inhibiting
aminopeptidase) together with the composition of the invention.
[0073] As an aminopeptidase inhibitor, amastatin, arphamenine A,
arphamenine B, bestatin and the like are known. These compounds may
be incorporated into a preparation, or may be separately
administered. When the aforementioned ingredient is not a peptide,
those skilled in the art can suitably identify the substance for
inactivating or degrading the ingredient, select an inhibitory
substance which inhibits an activity of substance for inactivating
or degrading the ingredient, and use or incorporate therein the
substance.
[0074] In a preparation, ingredients used for usual compositions as
additives other than the aforementioned additives may be used, and
amounts of these ingredients to be added may be usual amounts in
such a range that does not interfere with the effect of the present
invention.
[0075] The composition of the present invention may be also used
together with other ingredients in the treatment for disinfecting
Helicobacter Pylori. For example, in addition to 40 mg (b.i.d.) of
omepurazor and 1,500 mg (t.i.d.) of amoxycillin, 300 mg (t.i.d.) of
the composition of the present invention may be used together.
[0076] The present composition is also useful for treating
intractable digestive tract disorder, such as chronic peptic ulcer,
ulcerative colitis observed in many young men or women, Crohn's
disease and the like.
[0077] Then, the present invention will be explained in more detail
by way of Examples, but the present invention is not limited to
them.
EXAMPLES
Example 1
[0078] Method for Synthesizing Various Peptides
[0079] An agonist peptide (Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2
(SLp-NH.sub.2)) and a control peptide
(Leu-Ser-Ile-Gly-Arg-Leu-NH.sub.2 (LSp-NH.sub.2)) used in Examples
were synthesized according to the known method (Carpino, L. A. et
al., J. Org. Chem., 37, 3404-3409, 1972).
[0080] Synthesis of Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ ID NO: 1,
SLp-NH.sub.2)
[0081] 1.33 g (0.17 meq/g) of Fmoc-PAL-PEG-PS-resin (PE BIOSYSTEMS)
was weighted, and then 10 mL of dimethylformamide was added thereto
to stand for 2 to 3 hours. After the resin was expanded and filled
into a column for synthesizing a peptide.
[0082] 283 mg of Fmoc-L-Leu-OH (WAKO), 519 mg of Fmoc-L-Arg(Pbf)-OH
(PE BIOSYSTEMS), 238 mg of Fmoc-L-Gly-OH (BACHEM), 283 mg of
Fmoc-L-Ile-OH (WAKO), 283 mg of Fmoc-L-Leu-OH (WAKO) and 307 mg of
Fmoc-L-Ser(tBu)-OH (PE BIOSYSTEMS) were weighted in test tubes, and
each 380 mg of
HATU(O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyl-uroniumhexa-fluoroph-
osphate) (PE BIOSYSTEMS) was added to each test tube. The
aforementioned amino acids were arranged in an order from a
C-terminus, and synthesis was performed using peptide synthesizer
PIONEER (PE BIOSYSTEMS). After the synthesized peptide-resin was
treated with a mixed solution of
TFA-H.sub.2O-phenol-triisopropylsilane (8.8:0.5:0.5:0.2) for 3
hours, the resin was filtered, and then the filtrate was
recrystallized from ether to give a crude peptide. The crude
peptide was then purified by subjecting to HPLC (A: 0.02% TFA
containing H.sub.2O, B: 0.02%TFA containing 50% CH.sub.3CN). The
resulting fraction was lyophilized to give
Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2.
[0083] Leu-Ser-Ile-Gly-Arg-Leu-NH.sub.2 (SEO ID NO: 5,
LSp-NH.sub.2)
[0084] LSp-NH.sub.2 becomes an inactive substance by substituting
Ser of SLp-NH.sub.2 with Leu (Hollenberg, M. D., Trends Pharmacol.
Sci., 17, 3-6, 1996, Nystedt, S. et al., Proc. Natl. Acad. Sci.
USA, 91, 9208-12, 1994).
[0085] According to the procedure described above, a column for
synthesizing a peptide was prepared, 283 mg of Fmoc-L-Leu-OH
(WAKO), 519 mg of Fmoc-L-Arg(Pbf)-OH (PE BIOSYSTEMS), 238 mg of
Fmoc-L-Gly-OH (BACHEM), 283 mg of Fmoc-L-Ile-OH (WAKO), 307 mg of
Fmoc-L-Ser(tBu)-OH (PE BIOSYSTEMS) and 283 mg of Fmoc-L-Leu-OH
(WAKO) were weighted in test tubes, and 380 mg of HATU was added to
each test tube. The aforementioned amino acids were arranged in an
order from a C-terminus, and synthesis was performed using a
peptide synthesizer PIONEER (PE BIOSYSTEMS). According to the
procedure described above, a crude peptide was obtained through the
synthesized peptide-resin, and purified by subjecting to HPLC. The
resulting fraction was lyophilized to give
Leu-Ser-Ile-Gly-Arg-Leu-NH.sub.2.
[0086] Moreover,
trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-ornithine-NH.sub.2 (SEQ ID NO:
2, tcLp-NH.sub.2) also used in the Examples which is an agonist
peptide was supplied from Professor Hollenberg M. D. in Medical
Department of Calgary University.
[0087] For example, other various peptides which are a ingredient
which activates PAR-2 are synthesized as follows:
[0088] Synthesis of Ser-Phe-Leu-Leu-Arg-NH.sub.2 (SEQ ID NO: 3,
SFp-NH.sub.2)
[0089] 1.33 g (0.17 meq/g) of the Fmoc-PAL-PEG-PS-resin (PE
BIOSYSTEMS) was weighted, 10 mL of dimethylformamide was added
thereto to stand for 2 to 3 hours, to expand a resin, and the resin
is filled into a column for synthesizing a peptide.
[0090] 519 mg of Fmoc-L-Arg(Pbf)-OH (PE BIOSYSTEMS), 283 mg of
Fmoc-L-Leu-OH (WAKO), 283 mg of Fmoc-L-Leu-OH (WAKO), 305 mg of
Fmoc-L-Phe-OH (WAKO), and 307 mg of Fmoc-L-Ser(tBu)-OH (PE
BIOSYSTEMS) are weighted in test tubes, and 380 mg of HATU (PE
BIOSYSTEMS) is added to each test tube. The aforementioned amino
acids are arranged in an order from a C-terminus, and synthesis was
performed using a peptide synthesizer PIONEER (PE BIOSYSTEMS).
After the synthesized peptide-resin is treated with a mixed
solution of TFA-H.sub.2O-phenol-triisopropylsilan- e
(8.8:0.5:0.5:0.2) for 3 hours, the resin is filtered, and then the
filtrate was recrystallized from ether to give a crude peptide. The
crude peptide is then purified by subjecting to HPLC (A: 0.02% TFA
containing H.sub.2O, B: 0.02% TFA containing 50% CH.sub.3CN). The
resulting fraction can be lyophilized to give
Ser-Phe-Leu-Leu-Arg-NH.sub.2.
[0091] Synthesis of Ser-Leu-Ile-Gly-Arg-Leu-OH (SEQ ID NO: 4,
SLp-OH)
[0092] 1.00 g (0.21 meq/g) of Fmoc-L-Leu-PEG-PS-resin (PE
BIOSYSTEMS) is weighted, 10 mL of dimethyl-formamide is added
thereto to stand for 2 to 3 hours to expand a resin, and then the
resin is filled into a column for synthesizing a peptide.
[0093] 519 mg of Fmoc-L-Arg(Pbf)-OH (PE BIOSYSTEMS), 238 mg of
Fmoc-L-Gly-OH (BACHEM), 283 mg of Fmoc-L-Ile-OH (WAKO), 283 mg of
Fmoc-L-Leu-OH (WAKO), and 307 mg of Fmoc-L-Ser(tBu)-OH (PE
BIOSYSTEMS) are weighted in test tubes, and 380 mg of HATU is added
to each test tube. The aforementioned amino acids are arranged in
an order from a C-terminus, and synthesis is performed using a
peptide synthesizer PIONEER (PE BIOSYSTEMS). According to the
procedure described above, a crude peptide is obtained through the
synthesized peptide-resin and purified by subjecting to HPLC. The
resulting fraction can be lyophilized to give
Ser-Leu-Ile-Gly-Arg-Leu-OH.
Example 2
[0094] Influence on Acceleration of Carbachol-Induced Gastric Acid
Secretion
[0095] Animal Used
[0096] In an experiment, male Wistar rats at 5 weeks of age were
used. After each animal was pre-bred for one week under the
circumstance of a room temperature of 23.+-.2.degree. C., the
humidity of 50.+-.5%, and the light-and-darkness cycle (light term:
from 07:00 to 19:00) of 12 hours, each animal was subjected to the
experiment. Water and solid feed were supplied freely during the
pre-breeding period and the experiment period.
[0097] Moreover, the number of animals used in the experiment was
4-14 animals in all cases, and the results were shown by
Mean.+-.Standard Error. The significant difference test was
performed by Tukey's multiple comparison test.
[0098] Method
[0099] A rat was anesthetized with ether after 18-24 hours of
fasting, and an abdomen was incised by about 1 cm below a lower end
of xiphoid sternum. Duodenum was pinched out of the opened
abdominal hole, a part joining pylorus and duodenum was ligated,
and the incised abdomen was sutured. After 30 minutes, the rat was
exsanguinated to kill, the stomach was isolated, and gastric juice
was collected. After the collected gastric juice was filtered, the
acidity in the gastric juice was measured by a titration method.
Carbachol (60 .mu.g/kg) was administered subcutaneously immediately
after pylorus ligation, and amastatin (2.5 .mu.mol/kg) was
administered intravenously at 1 min after carbachol administration,
and SLp-NH.sub.2 or LSp-NH.sub.2 was administered intravenously at
1 min after amastatin administration, and then the effect on the
gastric acid secretion accelerated by administration of carbachol
was investigated.
[0100] Results
[0101] The results are shown in FIG. 1. In FIG. 1, a vertical axis
shows an amount of secreted gastric acid (.mu.mol/30 min), and a
horizontal axis shows an administered drug and an amount thereof (V
indicates administration of a vehicle). As shown in FIG. 1,
SLp-NH.sub.2 which is a PAR-2 agonist peptide inhibited
dose-dependently the gastric acid secretion accelerated by
administration of carbachol at a dose of 1.25 to 5 .mu.mol/kg. To
the contrary, LSp-NH.sub.2 which is a control peptide for
SLp-NH.sub.2 did not affect the gastric acid secretion accelerated
by carbachol at a dose of 5 .mu.mol/kg.
Example 3
[0102] Influence on Mucin Secretion from Rat Gastric Mucosal
Cells
[0103] Method
[0104] The gastric pylorus was ligated by the same procedure as
described above. Amastatin (2.5 .mu.mol/kg) was administered
intravenously immediately after the ligation, and SLp-NH.sub.2,
LSp-NH.sub.2 or tcLP-NH.sub.2 was administered intravenously at 1
minute after administration of amastatin. 30 minutes after
ligation, the rats was exsanguinated to kill, the stomach was
isolated, and the gastric juice was collected. The collected sample
of gastric juice was centrifuged at 10000.times.g for 30 min, and
the supernatant was subjected to ultrafiltration with Millipore MC
FREE (MW10000), followed by lyophilization. 2M TFA was added to the
lyophilized sample, which was hydrolyzed under the conditions at
100.degree. C. for 4 hours. Centrifugal separation was then
performed and the supernatant was evaporated to dryness. 200 .mu.L
of 0.1 M Tris-HCl was added to the evaporated and dried sample to
dissolve it. After 150 .mu.L of a reaction solution containing
galactose oxidase (1 U), peroxidase (0.5 mU) and HPPA (0.25
.mu.mol) was added to 50 .mu.L of the sample and the mixture was
incubated at 37.degree. C. for 30 minutes, an amount of galactose
was measured at an excitation wavelength of 320 nm and an
fluorescence wavelength of 405 nm.
[0105] Results
[0106] The results are shown in FIG. 2. In FIG. 2, a vertical axis
shows an amount of secreted mucin (ng galactose), and a horizontal
axis shows an administered drug and a dose thereof (V indicates the
administration of a vehicle). As shown in FIG. 2, SLp-NH.sub.2
accelerated dose-dependently the mucin secretion from rat gastric
mucosal cells at a dose of 0.02 to 5 .mu.mol/kg. The tcLp-NH.sub.2,
an agonist peptide which is more specific for PAR-2 than
SLp-NH.sub.2, also accelerated the mucin secretion like
SLp-NH.sub.2. To the contrary, LSp-NH.sub.2 which is a control
peptide for SLp-NH.sub.2 did not affect mucin secretion.
Example 4
[0107] Influence on Ethanol- and Hydrochloric Acid-Ethanol-Induced
Gastric Mucosa Lesion
[0108] Method
[0109] Preparation of ethanol- and hydrochloric
acid-ethanol-induced gastric mucosa lesion was performed according
to the method of Robert et al. (Robert, A. et al., Gastroenteral,
77, 433-443, 1979). That is, after the rats were fasted for 18 to
24 hours, 1 mL of 75% ethanol or 60% ethanol containing 150 mM
hydrochloric acid was administered orally. Rats were exsanguinated
to kill after 60 min and their stomaches were isolated. The
isolated stomach was incised along with greater curvature, washed
and fixed with 10% formaldehyde, and an area of gastric mucosa
lesion was measured using Image analyzing software, Mac acpect
(Mitani corporation, Chiba prefecture). SLp-NH.sub.2 was
administered intravenously at 5 minutes before administration of
75% ethanol or 60% ethanol containing 150 mM hydrochloric acid.
Amastatin (2.5 .mu.mol/kg) was administered at 1 minute before
administration of SLp-NH.sub.2.
[0110] Results
[0111] The results of administration of 75% ethanol are shown in
FIG. 3, and the results of administration of 60% ethanol containing
150 mM hydrochloric acid are shown in FIG. 4. In FIGS. 3 and 4, a
vertical axis shows the area (cm.sup.2) of gastric mucosa lesion,
and a horizontal axis shows an administered drug and a dose thereof
(V indicates administration of a vehicle).
[0112] As shown in FIG. 3, SLp-NH.sub.2 showed the protective
effect on the gastric mucosa lesion by ethanol at a dose of 0.25
and 0.5 .mu.mol/kg. As shown in FIG. 4, at a dose of 0.25 and 0.5
.mu.mol/kg, the protective effect was shown also on the lesion in
gastric mucosa by hydrochloric acid-ethanol as well as the lesion
in gastric mucosa by ethanol.
Example 5
[0113] Tablet
[0114] A tablet was prepared by the conventional method according
to the following formulation.
1 Microcrystalline cellulose 18 mg SLp-NH.sub.2 15 mg
Low-substituted hydroxypropyl cellulose 12 mg Hydroxypropylmethyl
cellulose 10 mg Magnesium stearate 1 mg Lactose q.s. Total 100
mg
Example 6
[0115] Tablet
[0116] A tablet was prepared by the conventional method according
to the following formulation.
2 Amastatin 20 mg Microcrystalline cellulose 18 mg SLp-NH.sub.2 15
mg Low-substituted hydroxypropyl cellulose 12 mg
Hydroxypropylmethyl cellulose 10 mg Magnesium stearate 1 mg Lactose
q.s. Total 100 mg
Example 7
[0117] Capsule
[0118] A capsule was prepared by the conventional method according
to the following formulation.
3 SLp-NH.sub.2 15 mg Low-substituted hydroxypropyl cellulose 15 mg
Closs-linked sodium carboxymethyl cellulose 5 mg Magnesium stearate
2 mg Lactose 63 mg Total 100 mg
Example 8
[0119] Capsule
[0120] A capsule was prepared by the conventional method according
to the following formulation.
4 SLp-NH.sub.2 15 mg Low-substituted hydroxypropyl cellulose 15 mg
Amastatin 5 mg Closs-linked sodium carboxymethy lcellulose 5 mg
Magnesium stearate 2 mg Lactose 63 mg Total 100 mg
Example 9
[0121] Injection
[0122] An injection was prepared by the conventional method
according to the following formulation.
5 Glucose 10 mg SLp-NH.sub.2 1 mg Amastatin 1 mg Water for
injection q.s. Total 200 ml
[0123] The preparations obtained in these Examples 5-9 may be used
as a composition for inhibiting secretion of gastric acid, a
composition for promoting secretion of digestive tract mucus,
compositions for protecting digestive tract mucosa, and a
composition for preventing or treating digestive organs
diseases.
INDUSTRIAL APPLICABILITY
[0124] The composition of the invention is an excellent preventive
or therapeutic drug having the gastric acid secretion inhibiting
activity, the mucus secretion promoting activity, the mucosa
protecting activity, the gastrointestinal tissue repairing activity
and the like.
[0125] Therefore, digestive organs diseases can be effectively
prevented and/or treated by using peptides
Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2,
trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-ornithine-NH.sub.2 and the
like, which are an ingredient which activates PAR-2. Moreover, the
durability of the activity of the aforementioned peptides can be
enhanced by using together with or incorporating a drug such as
peptidase inhibitor amastatin and the like, since the
aforementioned peptides are degraded by peptidase present in the
living body.
SEQUENCE LISTING FREE TEXT
[0126] SEQ ID NO: 1: Designed peptide having PAR-2 agonist
activity. The C-terminal amino acid residue is amidated.
[0127] SEQ ID NO: 2: Designed peptide having PAR-2 agonist
activity. Xaa at 1 is trans-cinnamoyl-Leu. Xaa at 6 is Orn. The
C-terminal amino acid residue is amidated.
[0128] SEQ ID NO: 3: Designed peptide having PAR-1 and PAR-2
agonist activity. The C-terminal amino acid residue is
amidated.
[0129] SEQ ID NO: 4: Designed peptide having PAR-2 agonist
activity. The C-terminal amino acid residue is hydroxylated.
[0130] SEQ ID NO: 5: Designed control peptide. The C-terminal amino
acid residue is amidated.
Sequence CWU 1
1
5 1 6 PRT Artificial Designed peptide having PAR-2 agonist
activity. The C-terminal amino acid residue is amidated. 1 Ser Leu
Ile Gly Arg Leu 1 5 2 6 PRT Artificial Designed peptide having
PAR-2 agonist activity. Xaa at 1 is trans-cinnamoyl-Leu. Xaa at 6
is Orn. The C-terminal amino acid residue is amidated. 2 Xaa Ile
Gly Arg Leu Xaa 1 5 3 5 PRT Artificial Designed peptide having
PAR-1 and PAR-2 agonist activity. The C-terminal amino acid residue
is amidated. 3 Ser Phe Leu Leu Arg 1 5 4 6 PRT Artificial Designed
peptide having PAR-2 agonist activity. The C-terminal amino acid
residue is hydroxylated. 4 Ser Leu Ile Gly Arg Leu 1 5 5 6 PRT
Artificial Designed control peptide. The C-terminal amino acid
residue is amidated. 5 Leu Ser Ile Gly Arg Leu 1 5
* * * * *