U.S. patent application number 10/169046 was filed with the patent office on 2003-10-30 for composition promoting lacrimal secretion.
Invention is credited to Araki, Hiromasa, Kawabata, Atsufumi, Kawai, Kenzo, Nishikawa, Hiroyuki, Nishimura, Sachiyo, Tanaka, Shuichi.
Application Number | 20030203849 10/169046 |
Document ID | / |
Family ID | 18495821 |
Filed Date | 2003-10-30 |
United States Patent
Application |
20030203849 |
Kind Code |
A1 |
Araki, Hiromasa ; et
al. |
October 30, 2003 |
Composition promoting lacrimal secretion
Abstract
A composition for promoting lacrimal secretion which can be used
safely and effectively in the lacrimal secretion promoting therapy,
not in the conventional supplemental therapy of lacrimal fluid
components is provided. The composition comprises a component which
activates PAR-2. Also, a contact lens which retains and/or contains
said composition for promoting lacrimal secretion is provided.
Inventors: |
Araki, Hiromasa;
(Yamatokoriyama-shi, Nara, JP) ; Kawabata, Atsufumi;
(Yamatotakada-shi, Nara, JP) ; Tanaka, Shuichi;
(Tajiro-cho, Sennan-gun, Osaka, JP) ; Kawai, Kenzo;
(Matsubara-shi, Osaka, JP) ; Nishimura, Sachiyo;
(Sakurai-shi, Nara, JP) ; Nishikawa, Hiroyuki;
(Kashiba-shi, Nara, JP) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.
624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Family ID: |
18495821 |
Appl. No.: |
10/169046 |
Filed: |
June 27, 2002 |
PCT Filed: |
December 8, 2000 |
PCT NO: |
PCT/JP00/08687 |
Current U.S.
Class: |
514/20.8 |
Current CPC
Class: |
A61K 38/482 20130101;
A61P 27/02 20180101; A61L 27/227 20130101; A61K 38/06 20130101;
A61P 43/00 20180101; A61K 38/177 20130101; G02B 1/043 20130101;
A61K 38/4826 20130101; A61K 38/08 20130101 |
Class at
Publication: |
514/17 |
International
Class: |
A61K 038/08 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 27, 1999 |
JP |
11/369996 |
Claims
What is claimed is:
1. A composition for promoting lacrimal secretion comprising a
component which activates PAR-2.
2. The composition for promoting lacrimal secretion according to
claim 1, wherein the component is a peptide.
3. The composition for promoting lacrimal secretion according to
claim 2, wherein the peptide comprises a sequence selected from the
group consisting of Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ ID NO:
1), Ser-Leu-Ile-Gly-Arg-Leu-OH (SEQ ID NO: 2) and
trans-cynnamoyl-Leu-Ile-Gly- -Arg-Leu-ornithine-NH.sub.2 (SEQ ID
NO: 3).
4. The composition for promoting lacrimal secretion according to
claim 1, wherein the component is a protein.
5. The composition for promoting lacrimal secretion according to
claim 4, wherein the protein is trypsin and/or tryptase.
6. The composition for promoting lacrimal secretion according to
any one of claims 1-5, wherein a substance which inhibits
inactivation or degradation of the component is used together
and/or is incorporated therein.
7. The composition for promoting lacrimal secretion according to
claim 6, wherein the substance is a peptidase inhibitor.
8. The composition for promoting lacrimal secretion according to
claim 7, wherein the peptidase inhibitor is amastatine.
9. The composition for promoting lacrimal secretion according to
any one of claims 1-8, which is formulated into a DDS
preparation.
10. The composition for promoting lacrimal secretion according to
any one of claims 1-9, which is formulated into a percutaneously
absorbing preparation.
11. The composition for promoting lacrimal secretion according to
any one of claims 1-9, which is an ophthalmic composition.
12. The composition for promoting lacrimal secretion according to
claim 11, wherein the ophthalmic composition has a form of a
washing solution, an eye drop, an ophthalmic ointment or an
ophthalmic gel.
13. The composition for promoting lacrimal secretion according to
claim 11, wherein the ophthalmic composition has a form of an eye
drop for contact lens, a preserving solution for contact lens or a
washing solution for contact lens.
14. A contact lens which retains and/or contains the composition
for promoting lacrimal secretion of any one of claims 1-8.
15. The contact lens according to claim 14 which retains and/or
contains the composition for promoting lacrimal secretion of any
one of claims 1-8 such that it is sustainedly released.
16. An agent for treating or preventing an ocular disease, which
comprises the composition for promoting lacrimal secretion of any
one of claims 1-8.
17 The. agent for treating or preventing an ocular disease
according to claim 16, wherein the ocular disease is dry eye,
ectocorneal desquamation, corneitis, corneal ulcer or
conjunctivitis.
Description
TECHNICAL FIELD
[0001] The present invention relates to a composition for promoting
lacrimal secretion for. treating and/or preventing an ocular
disease followed by lowered lacrimal secretion, that are, dry eye,
ectocorneal desquamation, corneitis, corneal ulcer, conjunctivitis
and the like. Furthermore, the present invention relates to a DDS
(drug delivery system) preparation, a percutaneously absorbing
preparation, a topical ophthalmic agent (such as eye drops,
ophthalmic ointments and the like) and a composition for a contact
lens which contain the composition for promoting lacrimal
secretion.
BACKGROUND ART
[0002] In recent years, dry eye patients have been increased with
spread of a contact lens and increase in a VDT-operation. Dry eye
is a disease exhibiting symptoms such as xerophthalmia, corneal
afflux, foreign body feeling, itching feeling and the like, which
results in corneal disorders, in principal, due to a lowered
lacrimal secretion. In addition, it is said that when dry eye
becomes severe, it also causes paropsia and asthenopia.
[0003] It is believed as a cause of a lowered lacrimal secretion,
there are Riley-day syndrome, Shy-Drager syndrome, Sjogren's
syndrome, sarcoidosis, amyloidosis, sequela of radiotherapy,
lagophthalmos, vitamin A deficiency, Stevens-Johnson syndrome,
occular pemphigoid, blepharitis marginal, meibomitis, sequela of
intraoccular surgery, contact lens disorder, diabetic ectocorneal
disease, VDT-operation, driving over a long period of time and the
like.
[0004] The lacrimal fluid exists in a border portion where an
eyeball contacts with air, and constitutes a thin fluid layer
having a thickness of approximately 7 .mu.m which covers an
outermost layer of the eyeball. The lacrimal fluid has a
three-layered structure, which consists of, from an outer side, an
oily layer, an aqueous layer and a mucinous layer, and each layer
plays an important role in preventing the eyeball from dryness. The
aqueous layer, which occupies most of the lacrimal fluid thickness,
is prevented from the decrement by existing between the oily layer
and the mucinous layer to maintain the wettability of the eyeball.
The oily layer is in principle secreted from a gland existing
around an eyelid, which is called meibom gland, and prevents
moisture from evaporation by covering throughout the aqueous layer.
Accordingly, when the production of the oily layer is reduced due
to meibomitis, the aqueous layer becomes apt to evaporate and,
thereby, symptom of dry eye is exhibited. The mucinous layer covers
a hydrophobic ectocorneal surface to change the surface to
hydrophilic and, thereby, has the function of retaining the aqueous
layer on an ectocorneal surface.
[0005] The lacrimal fluid has various. functions in addition to
prevention of dry eye. Other functions of the lacrimal fluid
include, for example, protection of cornea and conjunctiva,
bacteriostatic action, prevention of infection with bacteria,
fungus, virus and the like, feeding of oxygen and a variety of
nutritions to cornea and removal of a carbon dioxide gas and
metabolites therefrom, dilution and removal of harmful stimuli in
the case where cornea and conjunctiva injured, transportation of
liquid components such as epidermal growth factors which
participate in wound healing and the like and hematocyte components
such as fibronectin and the like to the injured portion, retainment
of cornea and a conjunctival epithelial cell, regulation of wound
healing and the like.
[0006] At present, various artificial lacrimal fluid-type eye drops
have been sold for the purpose of treatment of the lowered lacrimal
secretion. However, many of them are a preparation comprising
inorganic salts and/or metal chelating agents for the purpose of
supplementing the lacrimal fluid and, therefore, although they are
temporarily effective to solve the dry feeling of eye followed by a
lowered lacrimal secretion, the effect is not sustained because
they do not affect the lacrimal secretion itself. In addition, it
is difficult to persistently remove unpleasantnesses such as
foreign body feeling and itching upon wearing the contact lens,
burning feeling of eye and the like due to dry eye. Furthermore,
when those having a lowered amount of oily secretion from meibom
gland increase a frequency of the treatment with eye drops, dry
feeling of eye becomes stronger due to washing out of the oily and
mucinous layers. This attributes to the problem due to a lacrimal
fluid components supplementing therapy, but not a lacrimal
secretion promoting therapy, which increases lacrimal secretion
itself.
[0007] Although there is, as the known lacrimal secretion promoting
therapy, a method, in which muscarinic drug such as pilocarpine as
a lacrimal secretion stimulating agent, it has not been a
satisfactory preparation yet because of the problems of side
effects and the like. Therefore, ophthalmologists and dry eye
patients could do nothing but take the lacrimal fluid supplementing
therapy while they knew the therapy has only temporal effects.
[0008] As stated above, the ophthalmologists and dry eye patients
have desired development of a composition for promoting lacrimal
secretion which can be used safely and effectively in the lacrimal
secretion promoting therapy, not in the conventional lacrimal fluid
components supplementing therapy.
[0009] On the other hand, it has been known that PAR
(Protease-activated receptor) belongs to a G-protein coupled seven
transmembrane receptor family and is a receptor which is 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 at a particular N-terminal site of an
extracellular domain by a protease to expose a new N-terminal. It
is believed that the newly exposed N-terminal becomes a linear
ligand and binds to an own active site to activate the receptor
(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).
[0010] It has been reported that there are 4 subtypes, PAR-1,
PAR-2, PAR-3 and PAR-4 in PAR and that they have different
functions from each other. It has been 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).
[0011] A site to be cleaved on the amino acid sequences of 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), PAR-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) has been known, and it has been
also known that PAR-1, PAR-2 and PAR-4 are activated by an
exogenous treatment with a synthetic peptide comprising 5-6 amino
acids which are synthesized based on an active amino acid sequence
at the site to be cleaved (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).
[0012] Activation of inositol 1,4,5-trisphosphate (IP3) and protein
kinase C series has been known as one of intracellular signals
through PAR-2 (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).
[0013] For PAR-2, an inflammatory response (Cirono, G. et al., J.
Exp. Med., 183, 821-827, 1996; Kawabata, A. et al., Br. J.
Pharmacol., 125, 419-422, 1998), and a constricting and relaxing
action in gastric blood vessel and trachea have been reported
(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). In
addition, it has been reported that PAR-2 is expressed in prostate,
small intestine, colon, liver, kidney and pancreas (Stephan, K. B.
et al., Biochem. J., 341, 1009-1016, 1996). However, PAR-2 relating
to the lacrimal secretion has not been reported yet, and the
present inventors have first demonstrated that a component which
activates PAR-2 (that is, an agonist) possesses the lacrimal
secretion promoting action.
OBJECT OF THE INVENTION
[0014] The present invention was done in light of the above prior
art, and an object of the present invention is to provide a safe
and effective composition for promoting lacrimal secretion. That
is, the object of the present invention is to provide a composition
possessing the novel lacrimal secretion promoting action, which can
solve a problem of side effects caused by conventional artificial
lacrimal fluid-type eye drops aiming at supplement of lacrimal
fluid components, and lacrimal secretory stimulating agents such as
muscarinic drugs or the like.
[0015] This and other objects as well as advantages of the present
invention will be illustrated below by referring to accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a graph illustrating the activity of PAR-2 agonist
peptide on the rat lacrimal secretion in vivo. **P<0.01 vs
SLp-NH.sub.2 (Tukey test).
[0017] FIG. 2 is a graph illustrating a dose-dependency of the rat
lacrimal secretion promoting activity by PAR-2 agonist peptide for
vivo. *<0.05, **<0.01 vs solvent (Tukey test).
SUMMARY OF THE INVENTION
[0018] The present inventors have investigated for the purpose of
developing a preferable drug for a composition for promoting
lacrimal secretion and, as the result, found that the lacrimal
secretion is caused by a component which activates PAR-2, which
resulted in completion of the present invention.
[0019] That is, the present invention provides:
[0020] (1) A composition for promoting lacrimal secretion
comprising a component which activates a PAR-2 receptor;
[0021] (2) The composition for promoting lacrimal secretion
according to (1), wherein the component is a peptide;
[0022] (3) The composition for promoting lacrimal secretion
according to (2), wherein the peptide comprises a sequence selected
from the group consisting of Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ
ID NO: 1), Ser-Leu-Ile-Gly-Arg-Leu-OH (SEQ ID NO: 2), and
trans-cinnamoyl-Leu-Ile-Gl- y-Arg-Leu-ornithine-NH.sub.2 (SEQ ID
NO: 3);
[0023] (4) The composition for promoting lacrimal secretion
according to (1), wherein the component is a protein;
[0024] (5) The composition for promoting lacrimal secretion
according to (4), wherein the protein is trypsin and/or
tryptase;
[0025] (6) The composition for promoting lacrimal secretion
according to any one of (1)-(5), wherein a substance which inhibits
inactivation or degradation of the component is used together
and/or incorporated therein;
[0026] (7) The composition for promoting lacrimal secretion
according to (6), wherein the substance is a peptidase
inhibitor;
[0027] (8) The composition for promoting lacrimal secretion
according to (7), wherein the peptidase inhibitor is
amastatine;
[0028] (9) The composition for promoting lacrimal secretion
according to any one of (1)-(8), which is formulated into a drug
delivery system (SDS) preparation;
[0029] (10) The composition for promoting lacrimal secretion
according to any one of (1)-(9), which is formulated into a
percutaneously absorbing preparation;
[0030] (11) The composition for promoting lacrimal secretion
according to any one of (1)-(9), which is an ophthalmic
composition;
[0031] (12) The composition for promoting lacrimal secretion
according to (11), wherein the ophthalmic composition has the form
of a washing solution, an eye drop, an ophthalmic ointment, or an
ophthalmic gel;
[0032] (13) The composition for promoting lacrimal secretion
according to (11), wherein the ophthalmic composition has the form
of an eye drop for contact lens, a preserving solution for contact
lens or a washing solution for contact lens;
[0033] (14) A contact lens which retains and/or contains the
composition for promoting lacrimal secretion according to any one
of (1)-(8);
[0034] (15) The contact lens according to (14), which retains
and/or contains the composition for promoting lacrimal secretion
according to any one of (1)-(8) so that it is sustainedly
released;
[0035] (16) An agent for treating or preventing an ocular disease,
which comprises the composition for promoting lacrimal secretion
according to any one of (1)-(8);
[0036] (17) The agent for treating or preventing an ocular disease
according to (16), wherein the ocular disease is dry eye,
ectocorneal desquamation, corneitis, corneal ulcer or
conjunctivitis.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The phrase "a component which activates PAR-2" refers to any
substance, which is naturally occurring or artificially
synthesized, possessing the ability to activate PAR-2 and,
includes, for example, a peptide, a protein, other compounds and
the like. Particularly, the component which activates PAR-2
includes, for example, trypsin and tryptase, that are naturally
occurring proteins which activate PAR-2; the
Ser-Phe-Leu-Leu-Arg-NH.sub.2 peptide (SEQ ID NO: 4) 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) and
which is known to have the agonist activity for human PAR-1
(Hollenberg, M. D., Molec. Pharmacol., 43, 921-930, 1993) and the
weak agonist activity for PAR-2 (Kawabata, A. et al., J. Pharmacol.
Exp. Ther., 288, 358-70, 1999) (hereinafter referred to as
"SFp-NH.sub.2"); the Ser-Leu-Ile-Gly-Arg-Leu-- NH.sub.2 peptide
(SEQ ID NO: 1) which is synthesized based on the previously
reported amino acid sequence of rat PAR-2 (Saifeddine, M. et al.,
Br. J. Pharmacol., 118(3), 521-530, 1996) and which is known to
have the agonist activity for rat PAR-2 (Hollenberg, M. D., Trends
Pharmacol. Sci., 17, 3-6, 1996; Nystedt, S. et al., Proc. Natl.
Acad. Sci. USA, 91, 9208-12, 1994) (hereinafter referred to as
"SLp-NH.sub.2"); the Ser-Leu-Ile-Gly-Arg-Leu-OH peptide (SEQ ID NO:
2) which is SLp-NH.sub.2 wherein the C-terminal is not amidated
(hereinafter referred to as "SLp-OH"); and the
trans-cynnamoyl-Leu-Ile-Gly-Arg-Leu-ornithine-NH.sub.2 peptide (SEQ
ID NO: 3) which is reported to specifically activate PAR-2
(hereinafter referred to as "tcLp-NH.sub.2") (Hollenberg, M. D. et
al., Can. J. Physiol. Pharmacol., 75, 832-41, 1997) and the like.
Furthermore, an antibody against PAR-2 or a fragment thereof may be
a protein or a peptide which specifically activates PAR-2.
[0038] In addition, the component which activates PAR-2 may be
obtained by screening various substances for the ability to
activate PAR-2 according to any known method. For example, a
substance which binds to PAR-2 may be screened by directly
detecting interaction between PAR-2 and the substance to be tested
using labeling with a radioisotope, surface plasmon resonance and
the like. In addition, a substance which induces signal
transmission through PAR-2 may be screened using an index of the
biological activity caused by activation of PAR-2 in a cell or
tissue expressing PAR-2. In addition, a substance which exhibits
the lacrimal secretion promoting action can be screened by using
the following method for measurement of an amount of lacrimal
fluid. For example, an assay method for PAR-2 activation is
described in Hollenberg, M. D., Can. J. Physiol. Pharmacol., 75,
832-841, 1997 and Kawabata, A., J. Pharmacol., Exp. Ther., 288,
358-370, 1999. The method for screening a substance which binds to
a receptor to induce an action (that is an agonist) has been 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).
[0039] The term "peptide" used herein 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 created or chemically synthesized. The peptide may be
synthesized according to the known method, for example, such as
that described in Carpino, L. A. et al., J. Org. Chem., 37,
3404-3409, 1972. Also, the peptide may be produced by using the
recombinant DNA technique. In addition, the peptide may contain a
modified or non-natural amino acid residue.
[0040] An amount of lacrimal fluid may be measured according to the
known method such as a method of Iga et al. using a rat (Iga, Y et
al., Jpn. J. Pharmacol., 78, 373-80, 1998). In particular, a rat is
anesthetized with pentobarbital (50 mg/kg, intraabdominal
administration), and a paper with 2 mm width for testing the human
lacrimal secretion function, the Schirmer test paper (Showa Yakuhin
Kako Co., Ltd.) is inserted into a lower eyelid of the rat. After a
period of time fixed has passed, the test paper is removed, and a
length of the wetted portion of the test paper is measured using a
caliper square. If a statistically significant increase of lacrimal
secretion is observed when a test substance is administered, it can
be said that the substance possesses the lacrimal secretion
promoting activity.
[0041] The composition for promoting lacrimal secretion of the
present invention is a composition comprising the component which
activates PAR-2, and is useful as an agent for treatment or
prevention of ocular diseases such as dry eye, ectocorneal
desquamation, corneitis, corneal ulcer, conjunctivitis and the
like, which can be treated or prevented by promoting the lacrimal
secretion. When the composition is used as the treating or
preventing agent, the composition for promoting lacrimal secretion
of the present invention can be used as such or can be used after
various treatments such as dilution with water and the like
thereto. Also, the composition for promoting lacrimal secretion can
be used by incorporation in a drug or a quasi-drug, particularly in
a composition for eye drops, a percutaneously absorbing preparation
or the like. An amount of the agent for promoting lacrimal
secretion to be incorporated may be appropriately selected
depending on a product, but may be usually 0.001-50% by weight, and
particularly 0.01-10% by weight in the case of a systemic
administration preparation. When the amount is below 0.001% by
weight, there is a possibility that the satisfactory lacrimal
secretion promoting activity is not observed. On the other hand,
when the amount exceeds 50% by weight, there is a possibility that
properties of the product itself such as the stability, the
flavoring property and the like are deteriorated.
[0042] The component which activates PAR-2, which is contained in
the composition for promoting lacrimal secretion of the present
invention, may be contained in the preparation as a
pharmaceutically acceptable salt thereof. The pharmaceutically
acceptable salt includes, for example, salts with bases such as an
inorganic base and an organic base, and acid addition salts with
acids such as an inorganic acid, an organic acid and a basic or
acidic amino acid and the like. The inorganic base includes, for
example, alkali metals such as sodium, potassium and the like,
alkaline-earth metals such as calcium, magnesium and the like, and
aluminum, ammonium and the like. The organic base includes, for
example, primary amines such as ethanolamine and the like,
secondary amines such as diethylamine, diethanolamine,
dicyclohexylamine and N,N'-dibenzylethylenediamine and the like,
tertiary amines such as trimethylamine, triethylamine, pyridine,
picoline, triethanolamine and the like, and the like. The inorganic
acid includes, for example, hydrochloric acid, hydrobromic acid,
nitric acid, sulfuric acid, phosphoric acid and the like. The
organic acid includes, for example, 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. The
basic amino acid includes, for example, arginine, lysine, ornithine
and the like. The acidic amino acid includes, for example, aspartic
acid, glutamic acid and the like.
[0043] When the peptide or protein is used as the component which
activates PAR-2, the durability of the activity of PAR-2 activation
can be enhanced by using together with a drug such as amastatine, a
peptidase inhibitor, or by incorporating amastatine into the
composition, because the peptide and protein are degraded by a
peptidase existing in a living body. When the component is not the
peptide, those skilled in the art can identify the substance which
inactivates or degrades the component, select another substance
which inhibits the substance, and use the selected substance
together or incorporated it in the composition.
[0044] As a mode of administrating a pharmaceutical composition of
the present invention, oral, topical ocular, intravenous,
transmucosal, transdermal, intramuscular, subcutaneous, or rectal
administration or the like can be properly selected, and the
pharmaceutical composition of the present invention can be
formulated into various preparations depending on the mode of the
administration. Although each preparation is described below, a
dosage form used in the present invention is not limited thereto,
and the composition of the present invention can be used as various
kinds of preparations which are ordinarily used in the field of
pharmaceutical preparation.
[0045] Systemic Administration Preparation
[0046] When the composition of the present invention is used as a
drug for treating the lowered lacrimal secretion, an oral dosage of
the component which activates PAR-2 is preferably in a range of
3-300 mg/kg, and more preferably in a range of 10-100 mg/kg. When
the systemic administration of the composition of the present
invention is conducted, particularly when it is intravenously
administered, the component should be administered such that the
effective blood concentration thereof becomes in a range of 2-200
.mu.g/mL, more preferably in a range of 5-100 .mu.g/mL, although it
may vary depending on sex, age and body type of the subject.
[0047] When the drug is orally administered, the dosage form of the
drug can be properly selected from the group consisting of powders,
granules, capsules, pills, tablets, elixirs, suspensions,
emulsions, syrups and the like. In addition, modification such as
sustained-releasing, stabilizing, easy-disintegrating,
hard-disintegrating, enterally solubilizing, and easy-absorbing
properties and the like may be applied to such the preparation
depending on the purpose. The dosage form in the case of the oral
administration includes, for example, chew, sublingual, buccal,
lozenges, ointments, attaching preparations, solution and the like,
and it can be properly selected therefrom. In addition,
modification such as sustained-releasing, stabilizing,
easy-disintegrating, hard-disintegrating, enterally solubilizing,
and easy-absorbing properties and the like may be applied to such
the preparation.
[0048] Known drug delivery system (DDS) techniques can be adopted
to each dosage form as described above. The term DDS preparation
herein refers to a preparation having an optimal form in light of
an administration route, bioavailability, side effect or the like,
such as a sustained-releasing preparation, a topically applying
preparation (such as a lozenge, a buccal tablet, a sublingual
tablet and the like), a controlled-releasing preparation, an
enteric preparation, a gastric-soluble. preparation and the
like.
[0049] Basically, as constituents of DDS, there are a drug, a
drug-releasing module, a film, and a therapeutic program.
Particularly, for each constituent, the drug has preferably a short
half-life such that the blood concentration of the drug is quickly
lowered when the releasing thereof is stopped, the film is
preferably not reactive with a biological tissue at the
administered portion, and the therapeutic program preferably
maintains the excellent drug concentration during a predetermined
period. Basically, the drug-releasing module has a drug reservoir,
a release-controlling portion, an energy source and a releasing
port or a releasing surface. These basic constituents may not be
all supplemented at the same time, and some. of them may be
optionally added or omitted to select the excellent form of
DDS.
[0050] The material to be used for DDS includes polymers,
cyclodextrin derivatives, lecithin and the like. The polymers
include an insoluble-polymer (silicone, ethylene-vinyl acetate
copolymer, ethylene-vinyl alcohol copolymer, ethyl cellulose,
cellulose acetate and the like), a water-soluble polymer and a
hydroxylgel-forming polymer (polyacrylamide, a cross-linked
polyhydroxyethyl methacrylate polymer, a cross-linked polyacrylic
polymer, polyvinyl alcohol, polyethylene oxide, a water-soluble
cellulose derivative, cross-linked poloxamer, chitin, chitosan and
the like), a gradually-dissolving polymer (ethyl cellulose, partial
ester of methyl vinyl ether-malic anhydride copolymer and the
like), a gastric-soluble polymer (hydroxypropylmethyl cellulose,
hydroxypropyl cellulose, carmellose sodium, macrogol, polyvinyl
pyrrolidone, dimethylaminoethyl methacrylate-methyl methacrylate
copolymer and the like), enteric polymer (hydroxypropylmethyl
cellulose phthalate, cellulose acetate phthalate,
hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl
cellulose, acrylates polymer and the like), and a bio-degradable
polymer (thermocoagulated- or -cross-linked albumin, cross-linked
gelatin, collagen, fibrin, polycyanoacrylate, polyglycolic acid,
polylactic acid, poly-.beta.-hydroxyacetic acid, polycaprolactone
and the like), and may be properly selected depending on the dosage
form.
[0051] Particularly, silicone, ethylene-vinyl acetate copolymer,
ethylene-vinyl alcohol copolymer, and partial ester of methyl vinyl
ether-maleic anhydride copolymer may be used for controlling
release of a drug, cellulose acetate may be used as a material of
an osmotic pump, ethyl cellulose, hydroxypropylmethyl cellulose,
hydroxypropyl cellulose and methyl cellulose may be used as a film
raw material of the sustained-release preparation, and the
cross-linked polyacryl polymer may be used as an adsorbing agent to
oral or ophthalmic mucosa.
[0052] In addition, the preparation can be produced by adding
additives such as solvents, excipients, coating agents, bases,
binding agents, lubricants, disintegrating agents, solution
adjuvants, suspending agents, thickening agents, emulsifying
agents, stabilizing agents, buffering agents, isotonicity adjusting
agents, soothing agents, preservatives, corrigents, flavors,
coloring agents and the like thereto depending on the dosage form
thereof (known dosage form such as oral preparation, injections,
suppository, percutaneously absorbing preparation and the
like).
[0053] Each of these additives is specifically exemplified below,
but is not limited thereto.
[0054] Solvents: purified water, water for injection, physiological
saline solution, peanut oil, ethanol, glycerin,
[0055] Excipients: starches, lactose, dextrose, white sugar,
crystalline cellulose, calcium sulfate, calcium carbonate, talc,
titanium oxide, trehalose, xylitol,
[0056] Coating agents: white sugar, gelatin, cellulose acetate
phthalate and polymers as described above,
[0057] Bases: vaseline, vegetable oils, macrogol, oil-in-water
emulsion base, water-in-oil emulsion base,
[0058] Binding agents: starch and derivatives thereof, cellulose
and derivatives thereof, naturally-occurring polymer compounds such
as gelatin, sodium alginate, tragacanth, gum arabic and the like,
synthetic polymer compounds such as polyvinyl pyrrolidone and the
like, dextrin, and hydroxypropylated starch,
[0059] Lubricants: stearic acid and salts thereof; talc, waxes,
wheat starch, macrogol, hydrogenated vegetable oils, sucrose fatty
acid ester, polyethylene glycol,
[0060] Disintegrating agents: starch and derivatives thereof, agar,
gelatin powder, sodium hydrogen carbonate, cellulose and
derivatives thereof, carmellose calcium, hydroxypropyl starch,
carboxymethyl cellulose and salts thereof as well as cross-linked
polymers thereof; low-substituted hydroxypropyl cellulose,
[0061] Solution adjuvants: cyclodextrin, ethanol, propylene glycol,
polyethylene glycol,
[0062] Suspending agents: gum arabic, tragacanth, sodium alginate,
aluminum monostearate, citric acid, various surfactants,
[0063] Thickening agents: carmellose sodium, polyvinyl pyrrolidone,
methyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol,
tragacanth, gum arabic, sodium alginate,
[0064] Emulsifying agents: gum arabic, cholesterol tragacanth,
methyl cellulose, various surfactants, lecithin,
[0065] Stabilizing agents: sodium hydrogen sulfite, ascorbic acid,
tocopherol chelating agents, inert gas, reducing substances,
[0066] Buffering agents: sodium hydrogenphosphate, sodium acetate,
boric acid,
[0067] Isotonicity adjusting agents: sodium chloride, glucose,
[0068] Soothing agents: procaine hydrochloride, lidocaine, benzyl
alcohol,
[0069] Preservatives: benzoic acid and salts thereof,
paraoxybenzoic acid esters, chlorobutanol, invert soap, benzyl
alcohol, phenol, thimerosal,
[0070] Corrigents: white sugar, saccharin, licorice extract,
sorbitol, xylitol, glycerin,
[0071] Flavors: bitter tincture, rose oil,
[0072] Coloring agents: water-soluble edible pigment, lake
pigment.
[0073] As described above, effects such as the sustained effective
blood concentration of a drug, enhancement of bioavailability and
the like can be expected by formulating a pharmaceutical into a DDS
preparation such as a sustained-releasing preparation, an enteric
preparation, a drug controlled-releasing preparation and the like.
However, there is a possibility that the component which activates
PAR-2 is inactivated or degraded in a living body and, as the
result, the desired effect is lowered or disappear. For example,
when the component which activates PAR-2 is a peptide, it is known
that many of such the peptides are degraded by aminopeptidase in a
living body (Godin, D. et al., Eur. J. Pharmacol., 253, 225-30,
1994). Accordingly, a substance, which inhibits a substance which
inactivates or degrades the component which activates PAR-2 (for
example, a substance which inhibits aminopeptidase), may be used
together with the composition for promoting lacrimal secretion of
the present invention to further sustain the effects of the
component.
[0074] Amastatine, Arphamenine A, Arphamenine B, and bestatin and
the like are known as an aminopeptidase inhibitor. These compounds
may be incorporated in the preparation, or may be administered
apart from the preparation. When the above component is not a
peptide, those skilled in the art can properly identify a substance
which inactivates or degrades the component, select another
substance which inhibits the substance, and can incorporated the
substance in the preparation or use together with the
preparation.
[0075] Ingredients other than those described above, which are used
in the conventional composition as an additive, may be used in the
preparation. An amount of these ingredients to be added may be a
usual amount without deteriorating the effect of the present
invention.
[0076] The composition for promoting lacrimal secretion of the
present invention. can be also applied to the skin. A preparation
to be applied to the skin is not particularly limited to, but
includes lotions, creams, gels, ointments, paste, plaster,
attaching preparations, patch, cataplasm, tape, TTS (Transdermal
Therapeutic System) preparations and the like. An application site
is not particularly limited to, but includes breast, nether parts,
regions of back, leg, cheek, eyelid, lower eyelid, arm, neck and
the like. A percutaneously absorbing preparation herein refers to
all the preparations as described above in a broader sense, but
refers to a preparation having a support such as plaster, attaching
preparations, patch, cataplasm, tape, TTS preparations and the like
in a narrower sense.
[0077] Particularly, a sticky polymer which is used for the
percutaneously absorbing preparation having a support includes
acrylic series, rubber series, silicone series and the like, but is
not particularly limited thereto so long as it is biologically
acceptable.
[0078] As the acrylic series, although (co)polymers containing
alkyl (meth)acrylate as a main component may be suitably used,
copolymers of alkyl (meth)acrylate and a monomer which is
copolymerizable with said alkyl (meth)acrylate may be used. A ratio
of alkyl (meth)acrylate in the constituents of (co)polymers
containing alkyl (meth)acrylate as a main component is preferably
equal to or higher than 20% by weight.
[0079] Alkyl (meth)acrylate includes methyl acrylate, butyl
acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate,
2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl
acrylate, lauryl acrylate, stearyl acrylate, methyl methacrylate,
butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl
methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl
methacrylate, lauryl methacrylate, stearyl methacrylate and the
like, and they may be used alone or in combination thereof
[0080] The polymerizable monomer as described above is preferably a
functional monomer such as a monomer containing an alkoxy group
having an ether linkage on a side chain, a monomer having a hydroxy
group, a monomer having a carboxyl group, a monomer having an amido
group, a monomer having an amino group, a monomer having a sulfoxyl
group, a monomer having an alkoxy group, a monomer having a
nitrogen-containing heterocycle and the like. Embodiments of such
the monomer are described below.
[0081] The monomer containing an alkoxy group having an ether
linkage on a side chain includes, for example, methoxyethyl
(meth)acrylate, ethoxydiethyl (meth)acrylate,
methoxydiethyleneglycol (meth)acrylate, methoxypropylene glycol
(meth)acrylate and the like.
[0082] The monomer having a hydroxy group includes, for example,
hydroxyalkyl (meth)acrylates such as hydroxyethyl (meth)acrylate,
hydroxypropyl (meth)acrylate and the like.
[0083] The monomer having a carboxyl group includes, for example,
.alpha.,.beta.-unsaturated carboxylic acids such as (meth)acrylic
acid and the like, monoalkyl maleates such as butyl maleate and the
like, maleic acid (anhydride), itaconic acid, fumaric acid,
crotonic acid and the like.
[0084] The monomer having an amido group includes, for example,
alkyl (meth)acrylamides such as (meth)acrylamide, dimethyl
(meth)acrylamide, N-butylacrylamide, diethylacrylamide and the
like, N-alkoxy (methyl)acrylamides such as butoxymethylacrylamide,
ethoxymethylacrylamide and the like, and the like.
[0085] The monomer having an amino group includes, for example,
dimethylaminoacrylate and the like.
[0086] The monomer having a sulfoxyl group includes, for example,
styrenesulfonic acid, acrylsulfonic acid, sulfopropyl
(meth)acrylate, (meth)acryloyloxynaphthalenesulfonic acid,
acrylamidemethylpropanesulfoni- c acid and the like.
[0087] The monomer having an alkoxy group includes, for example,
methoxyethyl (meth)acrylate, tetrahydrofurfuryl (meth)acrylate,
methoxyethyleneglycol (meth)acrylate, methoxypolythyleneglycol
(meth)acrylate and the like.
[0088] The monomer having a nitrogen-containing heterocycle
includes, for example, vinylpyrrolidone, methyl vinylpyrrolidone,
vinylpiperazine, vinylimidazole and the like.
[0089] In addition to the monomers as described above, monomers
such as vinyl chloride, vinyl acetate, vinyl propionate, styrene,
.alpha.-methylstyrene, acrylonitrile, ethylene, propylene,
butadiene and the like may be used.
[0090] The (co)polymer containing alkyl (meth)acrylate as a main
component as described above is usually prepared by conducting
solution polymerization, in which the monomer as described above is
contained in the presence of a polymerization initiator. In the
case where solution polymerization is conducted, a solvent for
polymerization such as ethyl acetate and the like may be added to a
predetermined amount of various monomers, and the mixture may be
reacted, under the nitrogen atmosphere, at 50-90.degree. C. for
5-100 hours in a reaction vessel equipped, with a stirrer and a
condenser in the presence of a polymerization initiator such as
azobis- and peroxide-compounds and the like.
[0091] The organic solvent for polymerization includes, for
example, benzene, ethylbenzene, butylbenzene, toluene, xylene,
hexane, heptane, ethyl acetate, hydroxyethyl acetate, methyl
benzoate, acetone, methyl cellosolve, ethyleneglycol monoethyl
ether, methyl alcohol, propyl alcohol and the like. The azobis
polymerization initiator includes 2,2-azobis-iso-butyronitrile,
1,1'-azobis(cyclohexane-1-carbonitrile),
2,2'-azobis(2,4-dimethylvaleronitrile) and the like, and the
peroxide polymerization initiator includes, for example, lauroyl
peroxide, benzoyl peroxide and the like.
[0092] As the rubber series pressure-sensitive adhesive as
described above, for example, natural rubber, isoprene rubber,
polyisobutylene, polyvinyl ether, polyurethane, polyisoprene,
polybutadiene, styrene-butadiene copolymer, styrene-isoprene
copolymer, styrene-isoprene-styrene block copolymer and the like
may be used.
[0093] As the silicone series pressure-sensitive adhesive as
described above, for example, silicone rubber such as of
polyorgano-siloxane and the like may be used.
[0094] In addition, as the pressure-sensitive adhesive, those
generally used for preparing a percutaneously absorbing
preparation, such as described in JP-A 9-208605, JP-A 10-94595,
JP-A 10-94596, JP-A 10-298068 and the like may be used.
[0095] A layer of the pressure-sensitive adhesive as described
above may be formed on a sheet- or tape-shaped support. As the
support, those in which an amount of the percutaneously absorbing
drug contained in a layer of the pressure-sensitive adhesive is not
lowered due to the loss of the drug through a backside of the
support, that is, those comprised of a drug non-permeable material
may be suitably utilized.
[0096] As the support, films such as of nylon, polyvinyl chloride,
plasticized polyvinyl chloride, polyvinylidene chloride,
polyethylene, polyethylene terephthalate, polypropylene, cellulose
acetate, ethyl cellulose, placticized vinyl acetate-vinyl chloride
copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl
acrylate copolymer and polyurethane, a polyester/polyethylene-vinyl
acetate copolymer laminate, a polyethylene-vinyl acetate
copolymer/rayon nonwoven fabric laminate, a polyester nonwoven
fabric/polyester film laminate, a vinylon nonwoven fabric/polyester
film laminate (particularly, see JP-A 10-310521) and films such as
of an aluminum sheet and the like may be used, and these materials
may be as a single layer or a laminate comprised of two or more
thereof A thickness of the support is preferably equal to or
smaller than 2000 .mu.m, and more preferably 2-300 .mu.m.
[0097] The composition for promoting lacrimal secretion of the
present invention may be contained in finely-divided polymer
particles dispersed in a layer of the pressure-sensitive adhesive.
The finely-divided polymer particle is, for example, of
cross-linked polyvinyl pyrrolidone, cross-linked cellulose,
polystyrene, styrene-divinylbenzene copolymer or the like, and the
material of the finely-divided polymer particle is properly
selected depending on a kind of a drug and the like. A diameter of
the finely-divided polymer particle is preferably equal to or
smaller than 200 .mu.m, and more preferably equal to or smaller
than 50 .mu.m. The drug contained in the finely-divided polymer
particle may be existed in the solubilized or non-solubilized
state. The solvent to be used for incorporating a drug in the
finely-divided polymer particle may be properly selected depending
on a kind of a drug or finely-divided polymer particle, and
examples thereof include ethyl acetate, toluene, tetrahydrofuran
and the like.
[0098] In preparation of the percutaneously absorbing preparation
of the present invention, conventional methods for producing a
pressure-sensitive adhesive tape can be applied for forming a layer
of the pressure-sensitive adhesive, such as a solvent coating
method, a hot-melt coating method, an electron radiation curing
emulsion coating method and the like.
[0099] In the solvent coating method as described above, a layer of
the pressure-sensitive adhesive having a predetermined thickness
can be formed on a support by dissolving or dispersing a
pressure-sensitive adhesive, a drug and, if necessary, other
additive in a suitable solvent, coating the resulting solution or
dispersion on the surface of the support, and then drying the
solvent to remove. Alternatively, a layer of the pressure-sensitive
adhesive may be prepared by coating the solution or dispersion as
described above on a release paper and adhering the resulting layer
of the pressure-sensitive adhesive on the surface of a support
after drying. If necessary, the percutaneously absorbing
preparation in which a finely-divided polymer particle containing a
drug is dispersed in a layer of the pressure-sensitive adhesive can
be obtained by using a finely-divided polymer particle containing a
drug in advance. The solvent to be used includes, for example,
benzyl alcohol, butyl benzoate, isopropyl myristate, octanol,
propylene glycol, polypropylene glycol, ethylene glycol and the
like.
[0100] Alternatively, the solution or dispersion as described above
may be applied to a release paper on which a silicone resin or the
like is coated, and the release paper is dried and adhered. to a
support, without directly applying the solution or dispersion to
the surface of the support. Such the release paper may be used for
protecting the surface of a layer of the pressure-sensitive
adhesive of the percutaneously absorbing preparation such as of
tape and the like until use. For example, a release paper in which
the surface of a polyethylene terephthalate film is treated with
silicone may be used. A thickness of the release paper is
preferably equal to or smaller than 1000 .mu.m, and more preferably
10-300 .mu.m.
[0101] A thickness of a layer of the pressure-sensitive adhesive
may vary depending on an object of use and an application site and,
when a thickness becomes small, an adhering force thereof becomes
weak, and the content of a drug per unit area of the percutaneously
absorbing preparation becomes insufficient. On the other hand, when
a thickness becomes large, there is a possibility that a
drug-releasing rate is lowered since a drug contained in a layer of
the pressure-sensitive adhesive near a support does not
sufficiently diffuse. Specifically, a layer of the
pressure-sensitive adhesive is prepared such that it has a
thickness of preferably 3-1000 .mu.m, and more preferably 10-500
.mu.m. In addition, a crosslinking treatment may be applied to a
layer of the pressure-sensitive adhesive.
[0102] If necessary, additives such as plasticizer,
absorption-promoting agent, skin torpent, antioxidant and the like
may be added to a layer of the pressure-sensitive adhesive. An
amount of the additive to be used varies depending on a kind of an
additive and is preferably 1-50% by weight, and more preferably
1-10% by weight based on a total weight of a layer of the
pressure-sensitive adhesive. When the amount of the additive to be
used is smaller than 1% by weight, an adhering force-lowering
action becomes small. On the other hand, when the amount exceeds
50% by weight, there is a possibility that an adhering force to a
skin becomes too weak, and pressure-sensitive adhesive transfer is
caused due to lowering of cohesion or the like.
[0103] A placticizer can regulate an adhering force of a layer of
the pressure-sensitive adhesive to the skin and reduce irritation
upon peeling off from the skin. The plasticizer includes, for
example, diisopropyl adipate, phthalic acid ester, diethyl
sebacate, higher fatty acid esters, a softening agent described in
JP-A 10-179711 and the like.
[0104] An absorption-promoting agent includes a compound which
enhances the solubility or the dispersibility of a drug in a layer
of the pressure-sensitive adhesive, a compound which changes a
water-retaining ability of keratin, a keratin-softening ability, a
keratin-permeability, or the like, a compound which acts as a
carrier and the like.
[0105] The compound which enhances the solubility or the
dispersibility includes glycols such as ethylene glycol, diethylene
glycol propylene glycol triethylene glycol, polyethylene glycol,
polypropylene glycol and the like, oils and fats such as olive oil,
caster oil, squalene, lanolin and the like, and the like. The
compound which changes the water-retaining ability of keratin, the
keratin-softening ability, the keratin-permeability includes
1-dodecylazocycloheptane-2-one, oleic acid, isopropyl myristate,
middle-chain fatty acid monoglyceride, monoterpenes, 1-menthol,
d-limonene urea, allantoin, salicylic acid, methyloctyl sulfoxide,
dimethyllaurylamide, dodecylpyrrolidone, iso-sorbitol
dimethylacetamide, dimethyl sulfoxide, dimethylformamide and the
like. The compound which acts as a carrier includes, for example,
ethanol, iso-propanol, N-methyl-2-pyrrolidone, propylene glycol and
the like. In addition, benzyl nicotinate which is a hair pore
opening agent, dibutylhydroxytoluene which is an antioxidant, and
the like may be used. The additive or synergistic
absorption-promoting effect can be expected by using two or more of
absorption-promoting agents as described above together.
[0106] Besides, the additive includes hydrocarbons, various
surfactants, aliphatic alcohols such as myristyl, alcohol,
pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl
alcohol and the like, straight-chain fatty acids such as
pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic
acid, oleic acid and the like, and aliphatic esters such as methyl
oleate, ethyl oleate, propyl oleate, methyl stearate, ethyl
stearate, propyl stearate, butyl stearate, lauryl stearate,
myristyl stearate, nonadecanoic acid methyl ester and the like, and
the like.
[0107] A method for crosslinking includes a physical crosslinking
treatment with radiation such as ultraviolet ray, electron beam, X
ray, .beta. ray, .gamma. ray and the like, and a chemical
crosslinking treatment which uses crosslinking agents such as
polyisocyanate compound, organic peroxide, organometallic salt,
metal alcoholate, metal-chelating compound, isocyanate compound,
epoxy compound and the like. An amount of the crosslinking agent to
be added in a layer of the pressure-sensitive adhesive is
0.001-10%, and preferably 0.05-1%.
[0108] An amount of a drug to be contained in the percutaneously
absorbing preparation is properly set depending on a kind of a drug
and an application site and is usually in a range of 1-60% by
weight, preferably 2-40% by weight. When the content of a drug in
the percutaneously absorbing preparation is below 1% by weight,
release of a drug at an effective amount for treatment or
prevention can not be expected. On the other hand, when the content
of the drug exceeds 60% by weight, it is economically
disadvantageous because enhancement of the effect can not be
expected for increment of a drug. In addition, in the present
invention, a whole drug contained in the percutaneously absorbing
preparation is not necessarily dissolved in a layer of the
pressure-sensitive adhesive, and a drug can be contained at an
amount equal to or exceeding its solubility in a layer of the
pressure-sensitive adhesive and dispersed in the undissolved
state.
[0109] As the known percutaneously absorbing preparing techniques,
there are those described in JP-A 9-77658, JP-A 9-12448, JP-A
9-176000, JP-A 9-301853, JP-A 9-169635, JP-A 10-130172, JP-A
10-179711, JP-A 10-298067, JP-A 10-306023, JP-A 11-92361, JP-A
11-104229, JP-A 11-292794 and the like, and the composition for
promoting lacrimal secretion of the present invention may be
prepared by utilizing these techniques.
[0110] Ophthalmic Preparation for Topical Administration
[0111] The composition for promoting lacrimal secretion of the
present invention can be used as ophthalmic preparations for
topical administration such as eyewash, eye drops, ophthalmic
ointments, ophthalmic gels and the like.
[0112] In the case of an ophthalmic preparation for topical
administration, an amount of the composition for promoting lacrimal
secretion may be 0.00001-50% (w/v), preferably 0.0001-5% (w/v), and
particularly 0.001-0.01% (w/v). When the amount is below 0.00001%
(w/v), there is a possibility that the satisfactory lacrimal
secretion promoting action is not perceived. On the other hand,
when the amount exceeds 50% (w/v), there is a possibility that
properties of a product itself such as the stability and the like
is deteriorated. In the case of an aqueous eye drop, it is
preferable that an osmotic. pressure thereof is adjusted at 230-450
m0sm, and preferably 260-320 m0sm. In addition, it is suitable that
a pH of an aqueous eye drop is adjusted to around 3.5-8.5, and
preferably around 5.0-8.0.
[0113] It is said that an amount of lacrimal fluid on the surface
of an eye is usually around 7 .mu.L, and that a time during which
an amount of a drug is decreased to a half level due to dilution or
outflow by lacrimal fluid exchange on the surface of an eye is
around 7 minutes. In the case of the aqueous eye drop, it is
preferable that it is instilled one to several times per day,
because a drug storage capacity of conjunctival sac is 10-30 .mu.L,
thereby, a large amount of the drug is not storable in the solution
state.
[0114] In the case of ophthalmic topical administration, the dosage
form of the composition for promoting lacrimal secretion includes
solutions, ointments, ophthalmic inserting agents, gels, emulsions,
suspensions and solid eye drops and the like, and may be properly
selected therefrom. In addition, modifications such as
sustained-releasing, stabilizing and easy-absorbing properties and
the like may be further applied to such the preparations. These
dosage forms are sterilized, for example, by filtration through a
microorganism separating filter, heat sterilization or the like .
In addition, a size of a particle contained in ophthalmic ointments
or the like is preferably equal to or smaller than 75 .mu.m.
[0115] The technique of drug delivery system (DDS) may be adopted
for the dosage forms as described above. For example, a DDS
preparation may be prepared in which the composition for promoting
lacrimal secretion of the present invention is contained in an
alginic acid matrix between membranes which are controlled
releasing membranes of an insoluble ethylene-vinyl acetate
copolymer. Such a DDS preparation can be continuously placed inside
eyelids, and can continuously release a drug at a constant rate. A
rate of releasing a drug is preferably 0.1 .mu.g/h-10 mg/h, and
more preferably 1 .mu.g/h-100 .mu.g/h.
[0116] In the case of an ophthalmic preparation for topical
administration, a factor which influences on a contact time and a
residence time of a drug becomes important. For this purpose,
sustained release can be realized by adding a thickening agent to
the ophthalmic preparation for topical administration, or
formulating the ophthalmic preparation for topical administration
into an oily or aqueous suspension, an oily solution or the like.
For example, the ophthalmic preparation for topical administration
can be formulated into a viscous eye drop or ophthalmic ointment
with a gradually dissolving polymer (povidone and a water-soluble
polymer) or the like added. In addition, sustained releasing
property, absorbability and the like of a drug can be significantly
enhanced by encapsulating the drug in ointments and liposomes.
[0117] The buffer to be used in the aqueous eye drop is
particularly preferably a borate buffer. When the borate buffer is
used as the buffer, a solution having a lower irritation as
compared with the case where other buffers, for example, a
phosphate buffer is used. Upon this, an amount of borate to be
added is 0.01-10% (w/v), preferably 0.1-4% (w/v), and more
preferably 0.5-2% (w/v).
[0118] In addition, additives such as solvents, bases, solution
adjuvants, suspending agents, thickening agents, emulsifying
agents, stabilizing agents, buffering agents, isotonicity adjusting
agents, soothing agents, preservatives, corrigents, flavoring
agents, coloring agents, excipients, binding agents, lubricants and
the like can be added to a preparation, depending on the dosage
forms (known dosage forms such as solutions, ointments, ophthalmic
inserting agents, gels, emulsions, suspensions, solid eye drops and
the like). Additionally, various additives such as pH adjusting
agents, gelling agents, solubilizing agents,. surfactants,
sweetening agents, absorption-promoting agents, dispersing agents,
preservatives, solubilizing agents and the like can be used.
[0119] Each of these additives is illustrated by way of embodiments
below, but not limited thereto.
[0120] Solvents: distilled water, physiological saline solution,
vegetable oils, liquid paraffin, mineral oils, propylene glycol,
p-octyl dodecanol, ethanol, ethylene glycol, macrogol, glycerin,
olive oil, sesame oil, peanut oil, caster oil,
[0121] Isotonicity adjusting agents: sodium chloride, boric acid,
sodium citrate, potassium chloride, borax, propylene glycol,
glycerin, glucose, sorbitol, mannitol, trehalose,
[0122] Buffering agents: boric acid, phosphoric acid, acetic acid,
citric acid, carbonic acid, tartaric acid and salts thereof, borax,
sodium citrate, sodium glutamate, sodium aspartate,
[0123] Stabilizing agents: sodium sulfite, propylene glycol,
[0124] Chelating agents: edetic acid and salts thereof,
nitrilotriacetic acid and salts thereof,
trihydroxymethylaminomethane, citric acid, sodium
hexametaphosphate,
[0125] Thickening agents: glycerin, carboxyvinyl polymer,
chondroitin sulfate, polyvinyl alcohol, polyvinyl pyrrolidone,
hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose and salts
thereof, sodium alginate, macrogol 4000, gum arabic, gelatin,
[0126] Bases: vaseline, purified lanolin, zeren 50, plastibase,
macrogol, liquid paraffin polyethylene glycol, carboxymethyl
cellulose,
[0127] Gelling agents: carboxymethyl cellulose, methyl cellulose,
carboxyvinyl polymer, ethylene malic anhydride polymer,
polyoxyethylene-polyoxypropylene block copolymer, gellan gum,
[0128] Excipients: crystalline cellulose,
[0129] Binding agents: hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, gelatin, polyvinyl pyrrolidone,
[0130] Lubricants: magnesium stearate, hydrogenated caster oil,
talc,
[0131] Stabilizing agents: editates, sodium citrate, sodium
hydrogensulfite, ethylenediaminetetraacetates,
[0132] PH adjusting agents: hydrochloric acid, sodium hydroxide,
phosphoric acid, citric acid, malic acid, tartaric acid, fumaric
acid, lactic acid, succinic acid, ascorbic acid, acetic acid,
[0133] Binding agents: hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, gelatin,
[0134] Suspending agents:. methyl cellulose, sodium carboxymethyl
cellulose, carboxyvinyl polymer, hydroxypropylmethyl cellulose,
polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol,
sodium chondroitin sulfate, polysorbate 80,
[0135] Bactericides: benzethonium chloride, chlorhexidine
gluconate,
[0136] Antioxidants: sulfites, ascorbic acid, .alpha.-tocopherol,
cysteine,
[0137] Coloring agents: tar pigments, riboflavin, licorice
extracts, zinc oxide,
[0138] Wetting agents: terpenoids (menthol, borneol, camphor,
geraniol, anethole, limonene, eugenol).
[0139] In addition to the above additives, drugs such as
antibiotics, antivirals, anti-inflammatory drugs, antiallergics,
vasoconstrictors, local anesthetics, analgesics, intraocular
pressure-lowering agents, immunoregulators, vitamins and the like
can be incorporated in the composition for promoting lacrimal
secretion of the present invention, so long as they does not
deteriorate the object of the present invention.
[0140] Such drugs are illustrated by way of embodiments below, but
not limited thereto.
[0141] Antibiotics: aminoglucosides, quinolones, new quinolones,
macrolides, cephems,
[0142] Sulfa drugs: sulfamethoxazole, sulfisoxazole, sulfisomidine,
sulfadiazine, sulfadimethoxine, sulfamethoxypyridazine,
[0143] Antivirals: famciclovir, penciclovir, aciclovir,
[0144] Nonsteroidal anti-inflammatory drugs: indomethacin,
diclofenac, pranoprofen, tiaprofenic acid, tolfenamic acid
[0145] Steroidal anti-inflammatory drugs: prednisolone,
[0146] Anti-inflammatories: dipottasium glycyrrhizinate, allantoin,
.epsilon.-aminocaproic acid, berberine chloride, berberine sulfate,
sodium azulenesulfonate, zinc sulfate, zinc lactate, lysozyme
chloride,
[0147] Antiallergics: ketotifen, oxatomide, cetirizine, sodium
cromoglicate,
[0148] Antihistamines: mequitazine, chlorpheniramine maleate,
diphenhydramine hydrochloride,
[0149] Vasoconstrictors: naphazoline, tetrahydrozoline,
oxymethazoline, phenylephrine, ephedrines, epinephrine and the
like, and salts thereof,
[0150] Local anesthetics: lidocaine hydrochloride, procaine
hydrochloride, dibucaine hydrochloride,
[0151] Cholinolytics: belladonna alkaloid, flutropium bromide,
tropicamide,
[0152] Antiphlogistic enzymes: lysozyme chloride, serrapeptase,
bromelain,
[0153] Miotics: pilocarpine hydrochloride
[0154] Galenical extracts: barren-worts, licorice, oriental bezoar,
ginseng, coix seed, Japanese angelica root, bupleurum root,
cinnamon bark, schisandra fruit, lithospermum root,
[0155] Flavoring agents and refreshing agents: menthols, camphors,
borneols, eucaliptus, geraniols, fennels, peppermints,
[0156] Anti-cholino esterases: neostigmine methylsulfate.
[0157] In addition, in the ophthalmic preparation for topical
administration, the known vitamins, for example, vitamin A, vitamin
C, vitamin E, vitamin B.sub.1, B.sub.2, B.sub.6, B.sub.12, and the
like as well as derivatives thereof can be used alone or in
combination of two or more thereof Retinol as a derivative of
vitamin A, ascorbates as a derivative of vitamin C, tocopherol
succinate as a derivative of vitamin E, bisibutiamine as a
derivative of vitamin B.sub.1, flavin adenine dinucleotide as a
derivative of vitamin B.sub.2, salts of pyridoxine and pyridoxal as
a derivative of vitamin B.sub.6, hydroxocobalamin as a derivative
of vitamin B.sub.12, and the like can be used. In addition, other
vitamins such as nicotinates, pantothenates, biotin and the like
can be used.
[0158] In the eye drop, a preferable amount of vitamins to be added
is, 0.1-10% (w/v), preferably 0.25-5% (w/v) of vitamin A and
derivatives thereof, 0.01-0.5% (w/v), preferably 0.03-0.3% (w/v) of
vitamin B.sub.1 and derivatives thereof, 0.005-0.3% (w/v),
preferably 0.01-0.2% (w/v) of vitamin B.sub.2 and derivatives
thereof, 0.01-0.5% (w/v), preferably 0.03-0.3% (w/v) of vitamin
B.sub.6 and derivatives thereof, 0.000005-0.003% (w/v), preferably
0.00001-0.0015% (w/v) of vitamin B.sub.12 and derivatives thereof,
0.005-0.2% (w/v), preferably 0.01-0.1% (w/v) of vitamin C and
derivatives thereof, and 0.005-0.2% (w/v), preferably 0.01-0.1%
(w/v) of vitamin E and derivatives thereof. When nicotinic acid
amide is used, the concentration thereof is preferably 0.01-1%
(w/v), and more preferably 0.05-0.5% (w/v).
[0159] In addition, amino acids as an osmoregulating chemical, a
nutrient source or the like, water-soluble polymers as an
osmoregulating chemical, a thickening agent or the like, neutral
salts as an osmoregulating chemical, lacrimal fluid ingredients
equivalent or the like and the like can be added.
[0160] The amino acids include, for example, .epsilon.-aminocaproic
acid, glutamic acid, lysine, histidine, leucine, methionine,
phenylalanine and the like. In addition, upon incorporation of the
amino acid in the aqueous eye drop composition of the present
invention, the amino acids may be added as such or in the form of
salts thereof. Such salts include, for example, sodium glutamate,
lysine hydrochloride, histidine hydrochloride and the like. When
the amino acid is used, the concentration thereof is preferably
0.01-1% (w/v), and more preferably 0.05-0.5% (w/v).
[0161] The water-soluble polymers include, for example, polyvinyl
pyrrolidone, hydroxypropylmethyl cellulose, polyvinyl alcohol,
carboxymethyl cellulose and the like. The concentration of the
water-soluble polymer is preferably 0.1-5% (w/v), and more
preferably 0.3-3% (w/v).
[0162] The neutral salts include, for example, sodium chloride,
calcium chloride, magnesium chloride, sodium sulfate, calcium
sulfate, magnesium sulfate, sodium nitrate, calcium nitrate and
magnesium nitrate, and particularly preferred among them are sodium
chloride, calcium chloride, magnesium chloride and magnesium
sulfate. Preferably, the concentration of the neutral salts should
be determined considering the osmotic pressure.
[0163] The solution adjuvants may be used in the ophthalmic
preparation for topical administration of the present invention.
The solution adjuvants include, for example, cyclodextrin,
polyvinyl pyrrolidone, caffeine, propylene glycol, benzyl benzoate,
ethanol, trisaminomethane, mannitol, sodium carbonate, sodium
citrate, taurine, nonionic surfactants such as
polyoxyethylenesorbitan mono higher fatty acid ester
(polyoxypolyoxyethylenesorbitan monooleate,
polyoxyethyleneoxystearic acid triglyceride and the like),
polyethylene glycol, polyoxyethylene hydrogenated castor oil,
polyoxyethylenesorbitan monooleate, polyoxyethylene monostearyl
polyoxyethylene lauryl. ether, monolaurate decaglyceryl,
polyoxyethylene polyoxypropylene glycol and the like. The nonionic
surfactants to be used in the eye drop and the like are known to
have the relatively low irritation for mucosa and cornea and,
therefore, they are widely used. The concentration of the nonionic
surfactant is preferably 0.01-10% (w/v), more preferably 0.05-5%
(w/v), and yet more preferably 0.1-2% (w/v). Other surfactants
include anionic surfactants (alkyl sulfate, sodium lauryl sulfate,
sodium lauroyl sarcosinate), but it is not preferable that they are
used in the eye drop because they have irritation for mucosa and
the like, although they have the strong dissolution aiding
action.
[0164] In addition, a preservative and an antiseptic are preferably
contained in the ophthalmic preparation for topical administration.
The preservative includes, for example, phenolic substances such as
phenol, cresol and paraoxybenzoic acid esters, alcohols such as
chlorobutanol, propylene glycol and the like, acidic substances
such as benzoic acid, dehydroacetic acid and the like and salts
thereof, quaternary ammonium salts such as benzalkonium chloride,
benzethonium chloride and the like, polyethyleneoxide-containing
high molecular quaternary ammonium compounds, thimerosal and the
like.
[0165] The antiseptic is preferably prepared in the concentration
between 0.0001%(w/v) and 5% (w/v), and includes quaternary ammonium
salts such as benzalkonium chloride, benzethonium chloride,
cetylpyridinium chloride and the like, paraoxybenzoic acid esters
such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl
paraoxybenzoate, butyl paraoxybenzoate and the like, benzyl
alcohol, phenethyl alcohol, chlorobutanol, thiomersal, thimerosal,
methylparaben, propylparaben, disodium editate, sorbic acid and
salts thereof, sodium dehydroacetate and the like.
[0166] In addition, as described above, sustained effects can be
expected by using together an aminopeptidase inhibitor because it
is known that many peptides which activate PAR are degraded by
aminopeptidase in a living body. Amastatine, Arphamenine A,
Arphamenine B, bestatin and the like are known as the
aminopeptidase inhibitor, and these compounds may be contained in
or may be used together with the preparation. Also, in the case
where the component as described above is not a peptide, the
substance which inactivates or degrades the component may be
contained in or may be used together with the preparation to
sustain the effects of the component.
[0167] For dry eye derived from abnormal lipid secretion. due to
meibomian glands dysfunction, a trace amount of oils such as caster
oil, liquid paraffin and the like may be added in the preparation,
in addition to the composition for promoting lacrimal secretion of
the present invention.
[0168] Ingredients which are used in the conventional composition
other than above ingredients can be used in the preparation, and an
amount of these ingredients to be added may be a usual amount so
long as they do not deteriorate the effects of the present
invention.
[0169] When an insoluble drug or the like is contained in the
composition for promoting lacrimal secretion of the present
invention, known techniques such as those described in JP-A
11-29463 may be used to obtain a stable aqueous suspension.
[0170] Preparation for Contact Lens
[0171] The composition for promoting lacrimal secretion of the
present invention can be applied to an eye drop for contact lens, a
washing solution for contact lens and a preserving solution for
contact lens, and a contact lens composition.
[0172] When the composition of the present invention is used as the
eye drop for contact lens, the washing solution for contact lens
and the preserving solution for contact lens, it is preferable that
surfactant is incorporated therein. The effect of preventing
adsorption of a phospholipid-like polymer to the contact lens can
be expected by incorporating the surfactant therein.
[0173] The surfactant includes nonionic surfactants such as
polyoxyethylene-polyoxypropylene block copolymer,
polyoxyethylene/polyoxy- propylene-substituted ethylenediamine,
Polysorbate 80, polyoxyethylene hydrogenated castor oil,
polyoxyethylenestearate and the like, amphoteric surfactants such
as alkylpolyaminoethyl glycine and the like, and anionic
surfactants such as alkylbenzene sulfonate, alkyl sulfate and the
like and, among them, nonionic surfactants are the most preferable
in light of safety to eyes. An amount of the surfactant to be
incorporated is preferably 0.001-5%, and more preferably
0.01-1%.
[0174] The eye drop for contact lens, the washing solution for
contact lens and the preserving solution for contact lens having a
generally used composition may be used, and the additives to be
used therein may be properly selected from the additives described
above for the ophthalmic preparation for topical administration.
The eye drop for contact lens, the washing solution for contact
lens and the preserving solution for contact lens may be produced
according to the method similar to that as described above for the
ophthalmic preparation for topical administration.
[0175] In addition, a drug-sustained releasing contact lens may be
produced in which the composition for promoting lacrimal secretion
of the present invention is retained in and/or adhered to a contact
lens.
[0176] The contact lens may be produced using the known materials.
For example materials for water-containing soft ophthalmic lens as
described in JP-A 9-80358, 2-hydroxyethyl methacrylate polymers as
described in JP-A 9-124715, ophthalmic lens materials as described
in JP-A 9-189887, molded ophthalmic collagen gels as described in
JP-A 11-197234, the hydrogel lens which is coated with a lipid
layer in advance as described in JP-A 9-101488 and the like may be
used. Additionally, known materials such as methacrylic acid ester
polymers, copolymers of oligosiloxanylalkyl(meth)acrylate
monomers/methacrylic acid ester monomer and the like may be
used.
[0177] Generally used contact lens such as hard or rigid
cornea-type lens, and gel, hydrogel or soft-type lens which are
produced from the above known materials may be used.
[0178] The drug sustained-releasing contact lens may be produced,
for example, by incorporating in or adhering to the contact lens
the composition for promoting lacrimal fluid secretion of the
present invention according to the known methods for producing the
drug sustained-releasing contact lens as described in JP-A 8-24325,
JP-A 11-24010, JP-A 10-339857 and the like.
[0179] Specifically, the drug sustained-releasing contact lens may
be produced by adhering to a part of the contact lens a
finely-divided or gel drug sustained-releasing agent which is
prepared from a component which activate PAR-2 and polymers such as
polyvinyl pyrrolidone, sodium hyaluronate and the like. In
addition, the drug sustained-releasing contact lens may be produced
by forming a drug reservoir such as by producing a contact lens
from a member which forms a front surface of the lens and a member
which forms a rear surface of the lens. Also, the contact lens of
the present invention may be produced according to the known
methods for producing the drug sustained-releasing contact lens
other than those described above.
[0180] The present invention will be further illustrated below by
way of Examples, but the present invention is not limited
thereto.
EXAMPLE 1
Method for Synthesizing Various Peptides
[0181] Various peptides, components of the present invention which
activate PAR-2, were synthesized according to the known method
(Carpino, L. A. et al., J. Org. Chem., 37, 3404-3409, 1972).
[0182] Method for Synthesizing Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2
(SEQ ID NO: 1, SLp-NH.sub.2)
[0183] 1.33 g (0.17 meq/g) of Fmoc-PAL-PEG-PS-resin (PE Biosystems)
was weighted, and 10 mL of dimethylformamide was added thereto to
stand for 2-3 hours, and the resin was swollen and filled in a
column for peptide synthesis.
[0184] The column for peptide synthesis was prepared according to
the above method, and 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) or 307 mg of Fmoc-L-Ser(tBu)-OH (PE Biosystems) was
separately weighted in a tube, and 380 mg of HATU
(O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (PE Biosystems) was added to each tube. Amino
acids described above were placed in an order from the C-terminal,
and synthesis was performed using a peptide synthesizer PIONEER (PE
Biosystems). The synthesized peptide-resin was treated with a
mixture of TFA-H.sub.2O-phenol-triisopropylsilane (8.8:0.5:0.5:0.2)
for 3 hours, the resin was filtrated, then the filtrate was
recrystallized from an ether to obtain a crude peptide. Then, the
crude peptide was purified by subjecting to HPLC (A: 0.02% TFA in
water; B:0.02% TFA in 50% CH.sub.3CN). The fraction containing
purified peptide was lyophihzed to obtain
Ser-Leu-Ile-Gly-Arg-Leu-NH.sub.2 (SEQ ID NO: 1).
[0185] Method for Synthesizing Ser-Leu-Ile-Gly-Arg-Leu-OH (SEQ ID
NO: 2, SLp-OH)
[0186] 1.00 g (0.21 meq/g) of Fmoc-L-Leu-PEG-PS-resin (PE
Biosystems) was weighted, and 10 mL of dimethylformamide was added
thereto to stand for 2-3 hours, and the resin was swollen and
filled in a column for peptide synthesis.
[0187] 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) or 307 mg of Fmoc-L-Ser(tBu)-OH (PE Biosystem)
was separately weighted in a tube, and 380 mg of HATU was added
thereto. Amino acids described above were placed in an order from
the C-terminal, and synthesis was performed using a peptide
synthesizer PIONEER. The crude peptide was obtained from the
synthesized peptide-resin and, thereafter, it was purified by
subjecting to HPLC. The fraction containing purified peptide was
lyophilized to obtain Ser-Leu-Ile-Gly-Arg-Leu-OH (SEQ ID NO:
2).
[0188] Method for Synthesizing
Trans-cynnamoyl-Leu-Ile-Gly-Arg-Leu-ornithi- ne-NH.sub.2 (SEQ ID
NO: 3)
[0189] This peptide was synthesized according to the known method
(Carpino, L. A. et al., J. Org. Chem., 37, 3404-3409, 1972).
[0190] Method for Synthesizing Ser-Phe-Leu-Leu-Arg-NH.sub.2 (SEQ ID
NO: 4)
[0191] 1.33 g (0.17 meq/g) of Fmoc-PAL-PEG-PS-resin (PE Biosystems)
was weighted, and 10 mL of dimethylformamide was added thereto to
stand for 2-3 hours, and the resin was swollen and filled in a
column for peptide synthesis.
[0192] 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) or 307 mg of Fmoc-L-Ser(tBu)-OH (PE
Biosystems) was separately weighted in tube, and 380 mg of HATU (PE
Biosystems) was added thereto. Amino acids described above were
placed in an order from the C-terminal, and synthesis was performed
using a peptide synthesizer PIONEER (PE Biosystems). The
synthesized peptide-resin was treated with a mixture of
TFA-H.sub.2O-phenol-triisopropylsilane (8.8:0.5:0.5:0.2) for 3
hours, filtrated, then the filtrate was recrystallized from an
ether to obtain a crude peptide. Then, the crude peptide was
purified by subjecting to HPLC (A: 0.02% TFA in water, B:0.02% TFA
in 50% CH.sub.3CN). The fraction containing purified peptide was
lyophilized to obtain Ser-Phe-Leu-Leu-Arg-NH.sub.2 (SEQ ID NO:
4).
[0193] Method for Synthesizing Leu-Arg-Gly-Ile-Leu-Ser-NH.sub.2
(SEQ ID NO: 5, LRp-NH.sub.2)
[0194] A column for peptide synthesis was prepared according to the
above method, and 307 mg of Fmoc-L-Ser(tBu)-OH (PE Biosystems), 283
mg of Fmoc-L-Leu-OH (WAKO), 283 mg of Fmoc-L-Ile-OH (WAKO), 238 mg
of Fmoc-L-Gly-OH (BACHEM), 519 mg of Fmoc-L-Arg(Pbf)-OH (PE
Biosystems), or 283 mg of Fmoc-L-Leu-OH (WAKO) was separately
weighted in a tube, and 380 mg of HATU was added thereto. Amino
acids described above were placed in an order from the C-terminal,
and synthesis was performed using a peptide synthesizer PIONEER.
The crude peptide was obtained from the synthesized peptide-resin
according to the method described above, and purified by subjecting
to HPLC. The fraction containing purified peptide was lyophilized
to obtain Leu-Arg-Gly-Ile-Leu-Ser-NH.sub.2 (SEQ ID NO: 5).
EXAMPLE 2
An Animal Which was Used in Experiments
[0195] Male Wistar-line rat at 6 weeks of age was used in
experiments. Each animal was housed for one week under the
environment of room temperature of 23.+-.2.degree. C., a humidity
of 50.+-.5% and a 12 hours light/dark cycle (light: 07:00-19:00)
and, thereafter, it was subjected to experiments. During the
housing and experiment period, the animal was fed a solid chaw and
water ad lib.
[0196] Four animals were used in Examples 3-4, and the results
thereof are shown in the mean.+-.S.E.M. The test of significance
was performed according to a Tukey's multiple comparison test.
EXAMPLE 3
[0197] The effect of PAR-2 agonist peptide on a rat lacrimal
secretion in vivo was investigated (FIG. 1).
[0198] An amount of rat lacrimal fluid was measured according to
the method of Iga et al. (Iga, Y et al., Jpn. J. Pharmacol., 78,
373-80, 1998). That is, the rat was anesthetized with pentobarbital
(50 mg/kg, intraabdominal administration), and a paper with 2 mm
width for testing human lacrimal secretion function, the Schirmer
test paper (Showa Yakuhin Kako Co., Ltd.) was inserted into a lower
eyelid of the rat After the period of time fixed has passed, the
test paper was removed, and a length of a wetted portion of the
test paper was measured using a caliper square. An amount of
lacrimal fluid was measured at 1, 2, 4, 6, 8 and 10 minutes after
intravenous administration of a solvent or PAR-associated
peptides.
[0199] When 5 .mu.mol/kg of a PAR-2 agonist peptide, SLp-NH.sub.2
was administered to the rat intravenously, significant promotion of
lacrimal secretion was observed with a peak 1 minute after the
intravenous. administration. Then, the effect of SLp-NH.sub.2, in
combination with amastatine, which is an aminopeptidase inhibitor,
on the lacrimal secretion promoting action of SLp-NH.sub.2 was
investigated, in light of that many PAR-2 agonist peptides are
known to be degraded by aminopeptidase (Godin, D. et al., Eur. J.
Pharmacol., 253, 225-30, 1994). Amastatine (Peptide Lab.) was
intravenously administered at 2.5 .mu.mol/kg 1 minute before
administration of SLp-NH.sub.2. As the result, a significant
promotion of lacrimal secretion having a peak 1 minute after the
administration was observed in SLp-NH.sub.2 alone. In the combined
treatment, however, the action thereof was more persistent than
that of SLp-NH.sub.2 alone, and a significant promotion of lacrimal
secretion was observed 8 and 10 minutes after the treatment as
compared with SLp-NH.sub.2 alone.
EXAMPLE 4
[0200] Dose-dependency in the promoting action of rat lacrimal
secretion by the PAR-2 agonist peptide in vivo was investigated
(FIG. 2).
[0201] An amount of lacrimal fluid was measured as described in
Example 3.
[0202] The SLp-NH.sub.2 promoted the rat lacrimal secretion in
doses of ranging from 1 to 5 .mu.mol/kg in a dose-dependent manner.
On the other hand, a control peptide, LRp-NH.sub.2 had no effect on
the rat lacrimal secretion even at 5.mu.mol/kg, and resulted in an
amount of lacrimal secretion similar to that of a
solvent-administrated group.
[0203] The formulations of the compositions of the present
invention manufactured according to the conventional method are
shown in each table in the following Examples.
EXAMPLE 5
[0204]
1 TABLE 1 Crystalline 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
Tablet
[0205]
2 TABLE 2 Amastatine 20 mg Crystalline 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
Capsule
[0206]
3 TABLE 3 SLp-NH.sub.2 15 mg Low-substituted hydroxypropyl
cellulose 15 mg Cross-linked sodium carboxymethyl cellulose 5 mg
Magnesium stearate 2 mg Lactose 63 mg Total 100 mg
EXAMPLE 8
Capsule
[0207]
4 TABLE 4 SLp-NH.sub.2 15 mg Low-substituted hydroxypropyl
cellulose 15 mg Amastatine 5 mg Cross-linked sodium carboxymethyl
cellulose 5 mg Magnesium stearate 2 mg Lactose 63 mg Total 100
mg
EXAMPLE 9
Injection
[0208]
5 TABLE 5 Dextrose 10 mg SLp-NH.sub.2 1 mg Amastatine 1 mg Purified
water for injection q.s. Total 200 mL
EXAMPLE 10
Eye Drop
[0209] (aqueous eye drop)
6 TABLE 6 SLp-NH.sub.2 10 mg Sodium chloride 90 mg Hydrochloric
acid q.s. Sodium hydroxide q.s. Sterilized purified water q.s.
Total 100 mL
EXAMPLE 11
Eye Drop
[0210] (aqueous eye drop)
7 TABLE 7 SLp-NH.sub.2 50 mg Boric acid 1700 mg Methyl
paraoxybenzoate 28 mg Propyl paraoxybenzoate 12 mg Sodium editate 5
mg Borax q.s. Sterilized purified water q.s. Total 100 mL
EXAMPLE 12
Eye Drop
[0211] (aqueous eye drop)
8 TABLE 8 SLp-NH.sub.2 1 mg Boric acid 700 mg Borax q.s. Sodium
chloride 510 mg Sodium editate 0.06 mg Benzalkonium chloride 0.005
mg Sterilized purified water q.s. Total 100 mL
EXAMPLE 13
Eye Drop
[0212] (aqueous eye drop)
9 TABLE 9 SLp-NH.sub.2 200 mg Allantoin 100 mg Chlorpheniramine
maleate 30 mg Boric acid 1700 mg Sodium citrate 220 mg
Chlorhexidine gluconate 5 mg Borax or hydrochloric acid q.s.
Sterilized purified water q.s. Total 100 mL
EXAMPLE 14
Eye Drop
[0213] (aqueous eye drop)
10 TABLE 10 SLp-NH.sub.2 1000 mg Pyridoxine hydrochloride 100 mg
Aminoethylsulfonic acid 1000 mg Chlorpheniramine maleate 50 mg
Boric acid 1000 mg Sodium citrate 220 mg Chlorhexidine gluconate
2.5 mg Sodium hydroxide or hydrochloric acid q.s. Sterilized
purified water q.s. Total 100 mL
EXAMPLE 15
Eye Drop
[0214] (aqueous eye drop)
11 TABLE 11 SLp-NH.sub.2 500 mg Cyanocobalamin 20 mg Potassium
L-aspartic acid 1000 mg Concentrated glycerol 1400 mg Sodium
citrate 200 mg Chlorhexidine gluconate 5 mg Sodium hydroxide or
q.s. hydrochloric acid Distilled purified water q.s. Total 100
mL
EXAMPLE 16
Eye Drop
[0215] (aqueous eye drop)
12 TABLE 12 SLp-NH.sub.2 2000 mg Flavin adenine dinucleotide 50 mg
Cyanocobalamin 20 mg Sodium chloride 900 mg Sodium citrate 200 mg
Chlorhexidine gluconate 2.5 mg Sodium hydroxide or q.s.
hydrochloric acid Sterilized purified water q.s. Total 100 mL
EXAMPLE 17
Eye Drop
[0216] (aqueous eye drop)
13 TABLE 13 SLp-NH.sub.2 250 mg Sodium acetate 100 mg Concentrated
glycerin 2600 mg Methyl paraoxybenzoate 20 mg Propyl
paraoxybenzoate 10 mg Chlorobutanol 250 mg Polyvinyl pyrrolidone
1000 mg Sterilized purified water q.s. Total 100 mL
EXAMPLE 18
Eye Drop
[0217] (aqueous eye drop)
14 TABLE 14 SLp-NH.sub.2 25 mg Concentrated glycerin 2600 mg
Polysorbate 80 100 mg Benzalkonium chloride 5 mg Sterilized
purified water q.s. Total 100 mL
EXAMPLE 19
Eye Drop
[0218] (aqueous eye drop)
15 TABLE 15 SLp-NH.sub.2 500 mg Boric acid 800 mg Borax 200 mg
Sodium hydroxide 500 mg Chlorobutanol 300 mg Sterilized purified
water q.s. Total 100 mL
EXAMPLE 20
Eye Drop
[0219] (aqueous eye drop)
16 TABLE 16 SLp-NH.sub.2 0.1 mg Sodium lauryl sulfate 600 mg
Polyoxyethylene lauryl 3000 mg ether (BL-25) Boric acid 1700 mg
Benzalkonium chloride 10 mg Sodium hydroxide q.s. Sterilized
purified water q.s. Total 100 mL
EXAMPLE 21
Eye Drop
[0220] (aqueous eye drop)
17 TABLE 17 SLp-NH.sub.2 150 mg Sodium acetate 50 mg Benzalkonium
chloride 5 mg Sodium chloride 650 mg Human serum albumin 100 mg
Sodium hydroxide q.s. Diluted hydrochloric acid q.s. Sterilized
purified water q.s. Total 100 mL
EXAMPLE 22
Eye Drop
[0221] (aqueous eye drop)
18 TABLE 18 SLp-NH.sub.2 700 mg Boric acid 2000 mg
.alpha.-cyclodextrin 5000 mg Borax q.s. Benzalkonium chloride 5 mg
Sterilized purified water q.s. Total 100 mL
EXAMPLE 23
Eye Drop
[0222] (aqueous eye drop)
19 TABLE 19 SLp-NH.sub.2 5000 mg Boric acid 1600 mg Borax 1000 mg
Polyvinyl pyrrolidone K30 2000 mg Caffeine 2000 mg Polyethylene
glycol (average 5000 mg molecular weight 4000) Methyl
paraoxybenzoate 260 mg Propyl paraoxybenzoate 140 mg Hydrochloric
acid q.s. Sterilized purified water q.s. Total 1000 mL
EXAMPLE 24
Eye Drop
[0223] (aqueous eye drop)
20 TABLE 20 SLp-NH.sub.2 25 mg Vitamin B2 50 mg Vitamin B6 100 mg
Vitamin B12 0.5 mg Naphazoline hydrochloride 50 mg Flutropium
bromide 20 mg Sterilized purified water q.s. Total 100 mL
EXAMPLE 25
Eye Drop
[0224] (aqueous eye drop)
21 TABLE 21 SLp-NH.sub.2 10 mg Vitamin B.sub.2 50 mg Vitamin
B.sub.6 100 mg Vitamin E 30 mg Oxymethazoline hydrochloride 25 mg
Fluticasone propionate 50 mg Lysozyme chloride 250 mg Lidocaine
hydrochloride 300 mg l-menthol 10 mg Sterilized purified water q.s.
Total 100 mL
EXAMPLE 26
Eye Drop
[0225] (aqueous eye drop)
22 TABLE 22 SLp-NH.sub.2 1 mg Allantoin 5 mg Neostigmine
methylsulfate 5 mg Flavin adenine dinucleotide 10 mg
.epsilon.-aminocapron 100 mg Boric acid 2000 mg Sodium hydroxide
q.s. Sterilized purified water q.s. Total 100 mL
EXAMPLE 27
Eye Drop
[0226] (aqueous suspended eye drop)
23 TABLE 23 SLp-NH.sub.2 1000 mg Sodium acetate 100 mg Sodium
chloride 900 mg Hydroxypropylmethyl cellulose 200 mg Methyl
paraoxybenzoate 20 mg Propyl paraoxybenzoate 10 mg 0.1 N
hydrochloric acid q.s. Sterilized purified water q.s. Total 100
mL
EXAMPLE 28
Eye Drop
[0227] (aqueous eye drop of dissolving before use-type)
[0228] [lyophilized preparation]
24 TABLE 24 SLp-NH.sub.2 100 mg Human serum albumin 1 g Sterilized
purified water q.s. Total 100 mL
[0229] [dissolving solution]
25 TABLE 25 Sodium acetate 50 mg Benzalkonium chloride 5 mg Sodium
chloride 650 mg Sodium hydroxide q.s. Diluted hydrochloric acid
q.s. Sterilized purified water q.s. Total 100 mL
EXAMPLE 29
Eye Drop
[0230] (oily eye drop)
26 TABLE 26 SLp-NH.sub.2 1 mg Cottonseed oil q.s. Total 10 mL
EXAMPLE 30
Eye Drop
[0231] (eye drop for contact lens)
27 TABLE 27 SLp-NH.sub.2 10 mg Poloxamer 407 100 mg Sodium chloride
500 mg Boric acid 700 mg Borax 50 mg Potassium sorbate 200 mg
Sterilized purified water q.s. Total 100 mL
EXAMPLE 31
Eye Drop
[0232] (eye drop for contact lens)
28 TABLE 28 SLp-NH.sub.2 500 mg Polysorbate 80 100 mg Sodium
chloride 500 mg Potassium chloride 150 mg Sodium
dihydrogenphosphate 200 mg Borax 300 mg Sterilized purified water
q.s. Total 100 mL
EXAMPLE 32
Eye Drop
[0233] (eye drop for contact lens)
29 TABLE 29 SLp-NH.sub.2 1 mg Polysorbate 80 100 mg Sodium chloride
500 mg Boric acid 750 mg Borax 50 mg Sterilized purified water q.s.
Total 100 mL
EXAMPLE 33
Eye Drop
[0234] (eye drop for contact lens)
30 TABLE 30 SLp-NH.sub.2 100 mg Poloxamer 407 100 mg Sodium
chloride 450 mg Potassium chloride 100 mg Sodium
dihydrogenphosphate 200 mg Borax 200 mg Alkylpolyaminoethyl glycine
10 mg Sterilized purified water q.s. Total 100 mL
EXAMPLE 34
Ophthalmic Ointment
[0235]
31 TABLE 31 SLp-NH.sub.2 1 g Glycerin 2 g Propylene glycol 1 g
Liquid paraffin 2 g Ethyl paraoxybenzoate 0.01 g Propyl
paraoxybenzoate 0.01 g Plastibase q.s. Total 100 g
EXAMPLE 35
Ophthalmic Ointment
[0236]
32 TABLE 32 SLp-NH.sub.2 0.1 g Liquid paraffin 5 g Ophthalmic white
vaseline q.s. Total 100.0 g
EXAMPLE 36
Ophthalmic Ointment
[0237]
33 TABLE 33 SLp-NH.sub.2 5 g Liquid paraffin 10 g White vaseline 80
g Purified lanolin 5 g Total 100.0 g
EXAMPLE 37
Ophthalmic Ointment
[0238]
34 TABLE 34 SLp-NH.sub.2 0.01 g Glycerin 2 g Propylene glycol 1 g
Liquid paraffin 2 g Methyl paraoxybenzoate 0.03 g Propyl
paraoxybenzoate 0.01 g White vaseline q.s. Total 100 g
EXAMPLE 38
Intraocularly Perfusing Washing Solution
[0239]
35 TABLE 35 SLp-NH.sub.2 100 mg Sodium chloride 500 mg Potassium
chloride 300 mg Potassium chloride (anhydrous) 100 mg Magnesium
sulfate (anhydrous) 100 mg Sodium acetate (trihydrate) 600 mg
Sodium citrate (anhydrous) 900 mg Sodium hydrogen carbonate
(anhydrous) 200 mg D-glucose (anhydrous) 150 mg 1N hydrochloric
acid q.s. Sterilized purified water q.s. Total 100 mL
Industrial Applicability
[0240] As stated above, a composition for promoting lacrimal
secretion of the present invention possesses the excellent lacrimal
secretion promoting action and, thus, is the excellent therapeutic
drug for dry eye resulted from the side effect of a drug, diseases,
lowered function of lacrimal secretion or the like. In addition,
the composition of the present invention can treat or prevent
xerophthalmia, corneal afflux, foreign body feeling, itching
feeling, paropsia, asthenopia, unpleasantness, burning feeling and
the like followed by dry eye.
[0241] In addition, the composition for promoting lacrimal
secretion of the present invention can be applied to an eye drop
for contact lens, a washing solution for contact lens and a
preserving solution for contact lens as well as a composition of
contact lens.
[0242] Sequence Listing Freetext
[0243] SEQ ID NO: 1
[0244] Designed peptide having PAR-2 agonist activity. The
C-terminal amino acid residue is amidated.
[0245] SEQ ID NO: 2
[0246] Designed peptide having PAR-2 agonist activity. The
C-terminal amino acid residue is hydroxylated.
[0247] SEQ ID NO: 3
[0248] Designed peptide having PAR-2 agonist activity. Xaa at 1 is
trans-cynnamoyl-Leu. Xaa at 6 is Orn.. The C-terminal amino acid
residue is amidated.
[0249] SEQ ID NO: 4
[0250] Designed peptide having PAR-1 and PAR-2 agonist activity.
The C-terminal amino acid residue is amidated.
[0251] SEQ ID NO: 5
[0252] Designed control peptide. The C-terminal amino acid residue
is amidated.
Sequence CWU 1
1
5 1 6 PRT Artificial Sequence AMIDATION 6 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 Sequence
MOD_RES 6 Designed peptide having PAR-2 agonist activity. The
C-terminal amino acid residue is hydroxylated. 2 Ser Leu Ile Gly
Arg Leu 1 5 3 6 PRT Artificial Sequence MOD_RES 1 MOD_RES 6
AMIDATION 6 Designed peptide having PAR-2 agonist activity. Xaa at
1 is trans-cynnamoyl-Leu. Xaa at 6 is Orn. The C-terminal amino
acid residue is amidated. 3 Xaa Ile Gly Arg Leu Xaa 1 5 4 5 PRT
Artificial Sequence AMIDATION 5 Designed peptide having PAR-1 and
PAR-2 agonist activity. The C-terminal amino acid residue is
amidated. 4 Ser Phe Leu Leu Arg 1 5 5 6 PRT Artificial Sequence
AMIDATION 6 Designed control peptide. The C-terminal amino acid
residue is amidated. 5 Leu Arg Gly Ile Leu Ser 1 5
* * * * *