U.S. patent application number 10/377743 was filed with the patent office on 2003-09-11 for method for treatment of external secretion disorders.
This patent application is currently assigned to R-TECH UENO, LTD.. Invention is credited to Ueno, Ryuji.
Application Number | 20030171438 10/377743 |
Document ID | / |
Family ID | 22504885 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030171438 |
Kind Code |
A1 |
Ueno, Ryuji |
September 11, 2003 |
Method for treatment of external secretion disorders
Abstract
Disclosed is a method for treatment of external secretion
disorders, which comprises administering a fatty acid derivative to
a subject in need of said treatment. The method of the present
invention is useful for treatment of at least one condition
selected from hypolacrimation including disorder of basal tear
secretion, dry-eye syndrome, hyposalivation and dry-mouth
syndrome.
Inventors: |
Ueno, Ryuji; (Montgomery,
MD) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 Pennsylvania Avenue, NW
Washington
DC
20037-3213
US
|
Assignee: |
R-TECH UENO, LTD.
|
Family ID: |
22504885 |
Appl. No.: |
10/377743 |
Filed: |
March 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10377743 |
Mar 4, 2003 |
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09615703 |
Jul 13, 2000 |
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6566398 |
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60143627 |
Jul 14, 1999 |
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Current U.S.
Class: |
514/573 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61P 1/04 20180101; A61P 11/00 20180101; A61K 31/201 20130101; A61K
31/5585 20130101; A61P 9/08 20180101; A61K 31/5575 20130101; A61P
13/00 20180101; A61P 27/02 20180101; A61P 1/02 20180101; A61P 17/00
20180101; A61K 9/0056 20130101; A61K 31/202 20130101; A61K 31/20
20130101; A61P 27/04 20180101; A61K 31/558 20130101; A61P 1/00
20180101; A61P 43/00 20180101; A61K 31/557 20130101; A61P 27/00
20180101; A61K 49/0008 20130101 |
Class at
Publication: |
514/573 |
International
Class: |
A61K 031/557 |
Claims
What is claimed is:
1. A method for treatment of external secretion disorders, which
comprises administering an effective amount of a fatty acid
derivative to a subject in need of said treatment.
2. The method of claim 1, wherein said external disorder is dry-eye
syndrome.
3. The method of claim 1, wherein said external disorder is
hypolacrimation.
4. The method of claim 1, wherein said external disorder is
dry-mouth syndrome.
5. The method of claim 1, wherein said external disorder is
hyposalivation.
6. The method of claim 1, wherein the fatty acid derivative is an
unsaturated fatty acid.
7. The method of claim 1, wherein the fatty acid derivative is a
prostaglandin like compound.
8. The method of claim 7, wherein the prostaglandin like compound
is a PG receptor agonist.
9. The method of claim 1, wherein the fatty acid derivative is the
one represented by the general formula (I): 8wherein W.sub.1,
W.sub.2 and W.sub.3 are carbon or oxygen atom, L, M and N are
hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or
oxo, wherein at least one of L and M is a group other than
hydrogen, and the five-membered ring may have at least one double
bond; A is --CH.sub.2OH, --COCH.sub.2OH, --COOH or its functional
derivative; B is single bond, --CH.sub.2--CH.sub.2--,
--CH.dbd.CH--, --C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2--- , or --CH.sub.2--C.ident.C--; Z is
9wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen, lower
alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4 and
R.sub.5 are not hydroxy and lower alkoxy at the same time; R.sub.1
is a divalent saturated or unsaturated lower-medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted by
halogen, oxo, hydroxy, lower alkyl, aryl or heterocyclic; and Ra is
a saturated or unsaturated lower-medium aliphatic hydrocarbon
residue, which is unsubstituted or substituted by halogen, oxo,
lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic or heterocyclic-oxy; cyclo(lower)alkyl;
cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic;
heterocyclic-oxy.
10. The method of claim 1, wherein the fatty acid derivative is the
one represented by the general formula (II): 10wherein L and M are
hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl or
oxo, wherein at least one of L and M is a group other than
hydrogen, and the five-membered ring may have at least one double
bond; A is --CH.sub.2OH, --COCH.sub.2OH, --COOH or its functional
derivative; B is single bond, --CH.sub.2--CH.sub.2--,
--CH.dbd.CH--, --C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2--, or --CH.sub.2--C.ident.C--; Z is 11wherein
R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen, lower alkyl,
lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4 and R.sub.5
are not hydroxy and lower alkoxy at the same time; X.sub.1 and
X.sub.2 are hydrogen, lower alkyl or halogen; R.sub.1 is a divalent
saturated or unsaturated lower-medium aliphatic hydrocarbon
residue, which is unsubstituted or substituted by halogen, oxo,
hydroxy, lower alkyl, aryl or heterocyclic; R.sub.2 is a single
bond or lower alkylene; and R.sub.3 is lower alkyl, lower alkoxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic or heterocyclic-oxy.
11. The method of claim 1, wherein the fatty acid derivative is the
one represented by the formula (III): 12wherein Q.sub.1 and Q.sub.2
are hydrogen or lower alkyl, or Q.sub.1 and Q.sub.2 are linked
together to form --(CH.sub.2).sub.n--wherein n is 1, 2 or 0, and
six-membered ring may have at least one double bond; A is
--CH.sub.2OH, --COCH.sub.2OH, --COOH or its functional derivative;
B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2--, or --CH.sub.2--C.ident.C--; Z is 13wherein
R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen, lower alkyl,
lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4 and R.sub.5
are not hydroxy and lower alkoxy at the same time; R.sub.1 is a
divalent saturated or unsaturated lower-medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted by
halogen, oxo, hydroxy, lower alkyl, aryl or heterocyclic; Ra is a
saturated or unsaturated lower-medium aliphatic hydrocarbon
residue, which is unsubstituted or substituted by halogen, oxo,
lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic or heterocyclic-oxy; cyclo(lower)alkyl;
cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic;
heterocyclic-oxy; and the six-memberd ring may optionally have one
or more double bonds and may optionally consist a conjugated
system.
12. The method of claim 1, which comprises administering
ophthalmically a composition comprising a fatty acid derivative
formulated in a dosage form suitable for ophthalmic
administration.
13. The method of claim 12, wherein said composition is formulated
as eye drops.
14. The method of claim 1, which comprises to orally administrate
to the subject a composition comprising a fatty acid derivative
formulated in a dosage form suitable for administrating into the
oral cavity.
15. The method of claim 14, wherein said composition is formulated
as a sublingual tablet.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method for treatment of
external secretion disorders, particularly, to a method for
treatment of hypolacrimation including dry-eye syndrome and
hyposalivation including dry-mouth syndrome.
BACKGROUND ART
[0002] External secretions are discharges that are discharged
directly from the exocrine glandular cells or through the excretory
ducts or the like onto the body surface or into a lumen. Tear and
saliva are the typical external secretions and secretions from the
nasal or the respiratory tract mucosa, secretions from the stomach
or the intestine, discharges from the vagina, perspiration, etc are
also included. Conditions resulting from external secretion
disorders include dryness of various parts of the body such as
"dry-eye syndrome" (xerophthalmia), "dry-mouth syndrome"
(xerostomia), "dry nose syndrome" (xeromycteria), "dry-skin
syndrome" (xeroderma), and "dry-vagina syndrome" (symptom of
vaginal dryness); and chronic pancreatitis, chronic gastritis, and
chronic bronchitis due to depression of the external secretion.
[0003] "Sjogren's syndrome", an autoimmune disease, is one of the
variety of known and unknown etiologic factors which may
responsible for external secretion disorders. Sjogren's syndrome is
characterized by dryness condition due to infiltration of
inflammatory cells into the acinus of the exocrine gland and around
the excretory duct, which results in destruction and atrophy of the
acinus and the epithelial cells of the duct. Typical symptoms
include eye and mouth dryness, as well as dryness of skin, nose,
throat, bronchia, vulva, and vagina. For example, dryness of the
respiratory tract may induce infections in the lung and sometimes
may cause serious disorders such as pneumonia that may lead to
death. The other major etiology is aging. Although the external
secretion disorders may cause serious diseases as mentioned above,
merely symptomatic treatment methods such as artificial hydration
have been available for the disorders so far. Therefore,
development of a fundamental treatment to improve the depressed
external secretion has been desired.
[0004] One of the diseases caused by the external secretion
disorders, and which has been a current keen interest in the
medical and pharmaceutical field, is hypolacrimation including
dry-eye syndrome.
[0005] Dry-eye syndrome is defined as a condition with decrease or
change in quality of tear irrespective of the presence or absence
of corneal and conjunctival lesion (Yamada et al., GANKI 43,
1289-1293(1992)). It include dry-eye conditions found in the
patients of hypolacrimation, alacrima, xerophthalmia, Sjogren's
syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome,
ocular pemphigoid, blepharitis marginal, and diabetes, etc.;
post-cataract surgery dry eye; allergic conjunctivitis-associated
dry eye; and age-related dry-eye syndrome. Further, dry-eye also
includes the conditions found in hypolacrimation patients induced
by long time visual display terminal (VDT) operations, room dryness
due to air-conditioning and the like.
[0006] There are various etiologies of the dry-eye syndrome,
including the above described and that have unidentified. However,
at present, only palliative treatments for the dry-eye syndrome
including administering an artificial tear solution to increase the
quantity of tear retained within the conjunctival sac thereby
relieve the subjective symptoms or protecting the eyes from dryness
have been available. It has been desired to provide compositions
which is capable of bringing satisfactory treatment, including
improvement of hypolacrimation.
[0007] The tear secretion is classified into basal tear secretion
and reflex tear secretion. Basal tear secretion is that under
ordinary conditions with the eyelid open, and is considered being
mainly from the accessory lacrimal glands e.g. Kraus gland and
Wolfring gland. On the other hand, reflux tear secretion is tear
secretion in response to some stimulation in the keratoconjunctival
surface, nasal mucosa, or the like, or that accompanied with mental
changes such as grief or joy. It is considered to be from the main
lacrimal gland. Considering the symptoms of the dry-eye syndrome,
improvement of the decreased basal tear secretion, i.e. tear
secretion under ordinary conditions with the eyelid open, is
particularly important.
[0008] Further, the diseases caused by external secretion disorders
also include hyposalivation, and it may be sometimes accompanied by
dry-mouth syndrome(xerostomia). In dry-mouth patients, the
decreased amount of saliva secretion causes dryness of the lip and
oral cavity and may induce thirst feeling, xerosis of tunica mucosa
oris, urtication, dysmaesesis, and dyspepsia. Also, in the patients
with dry-mouth syndrome, foods are likely to remain inside the
mouth and may result in dental caries.
[0009] There are a variety of etiologic factors which are
responsible for the dry-mouth syndrome. For example, systemic
factors include febrile disease, dehydration, endocrinopathy
(myxedema, Basedow's disease, diabetes insipidus, etc.) metabolic
disorders (diabetes, uremia, liver cirrhosis, etc.) deficiency of
Vitamin-A, B, autoimmune disease (Sjogren's syndrome, progressive
scleroderma, etc.) anemia, bleeding, aging, various medicaments
(sedatives, parasympatholytic drugs, antihistamines, etc.). Local
factors include sialadenitis, atrophy of salivary gland, sequela of
radio therapy, and malformation (ectodermal dysplasia, etc.) As
described above, there are a variety of known and unknown etiologic
factors responsible for the dry-mouth syndrome. However, at
present, only palliative treatments for the dry-mouth syndrome such
as drinking liquid all day long little by little, chewing gum or
the like, and using artificial saliva have been available. It has
been desired to provide a composition which is capable of bringing
fundamental treatment such that to improve the decreased saliva
secretion.
[0010] Generally, a healthy normal person discharges 1 to 1.5
litter of saliva a day through a pair of left and right major
salivary glands (including parotid gland, submandibular gland, and
sublingual gland) and minor salivary glands (including labial
glands, lingual glands, palatine glands, and buccal glands). Saliva
is discharged in response to a stimulant which may harm body to
dilute the same or to maintain the physiological pH value, as well
as helping mastication and deglutition of foods. Further, saliva
dissolves foods thereby makes a person taste them and helps him
smoothly utter words by keeping a wet state inside the mouth. There
are two types of saliva: one is the continuous type that keeps on
discharging a small amount without a particular stimulant and the
other is the reflective type that is discharged in response to
stimulation by food, gnatho-movement, taste and the like. In any
case, saliva secretion is one of the essential physiological
functions and hence improving the decreased saliva secretion is
particularly important in treating the dry-mouth syndrome.
[0011] In the past, some of fatty acids had been rated as
essential, and enough amount of them were required to be taken from
the nutrient point of view. Recently, bioactivities of a variety of
fatty acids have been studied and the activities of linoleic acid,
arachidonic acid, .alpha.-linolenic acid, eicosapentaenoic
acid(EPA), and docosahexaenoic acid (DHA) have attracted the
attention. linoleic acid is converted through
di-homo-.gamma.-linolenic acid to arachidonic acid;
.alpha.-linolenic acid is converted through eicosapentaenoic
acid(EPA) to docosahexaenoic acid (DHA); di-homo-.gamma.-linolenic
acid is converted into type 1 prostaglandin (PG.sub.1), arachidonic
acid is converted into type 2 prostaglandin (PG.sub.2) or type 4
leukotriene (LT.sub.4), and eicosapentaenoic acid is converted into
type 3 prostaglandin or type 5 leukotriene (LT.sub.5) in vivo
respectively.
[0012] Prostaglandins (hereinafter, referred to as PG(s)) are
members of class of organic carboxylic acids, which are contained
in tissues or organs of human or most other mammalian, and exhibit
a wide range of physiological activity. PGs found in nature
(primary PGs) generally have a prostanoic acid skeleton as shown in
the formula (A): 1
[0013] On the other hand, some of synthetic analogues have a
modified skeleton. The primary PGs are classified to PGAs, PGBs,
PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the
structure of the five-membered ring moiety, and further classified
into the following three types by the number and position of the
unsaturated bond at the carbon chain moiety:
[0014] subscript 1: 13,14-unsaturated-15-OH
[0015] subscript 2: 5,6- and 13,14-diunsaturated-15-OH
[0016] subscript 3: 5,6-, 13,14-, and
17,18-triunsaturated-15-OH.
[0017] Further, the PGFs are classified, according to the
configuration of the hydroxyl group at the 9-position, intoa type
(the hydroxyl group is of an .alpha.-configuration) and .beta. type
(the hydroxyl group is of a .beta.-configuration).
[0018] In addition, some 15-keto (i.e. having an oxo group at
position 15 in place of the hydroxy group) prostaglandins and
13,14-dihydro-15-keto-p- rostaglandins are known as substances
naturally produced by enzymatic actions during in vivo metabolism
of primary PGs. 15-keto PGs have been disclosed in, for example,
EP-A-0281239(corresponds to JP-A-104040/89),
EP-A-0281480(corresponds to JP-A-52753/89), EP-A-0289349
(corresponds to JP-A-151552/89), EP-A-0453127(JP-A-58992/95) and
EP-A-0690049(corresponds to JP-A-48665/96). These cited references
are herein incorporated by reference.
[0019] For example, when a primary type PG such as PGE.sub.2 or
PGF.sub.2a which is a fatty acid derivative is instilled to the
eyes at a stimulating amount which induces conjunctival hyperemia,
lacrimation will occur simultaneously with the hyperemia. However,
at an amount as low as that does not induce any conjunctival
hyperemia, it is not known about the effect of the fatty acid
derivatives including PGs on the tear secretion, basal tear
secretion which is not affected by a stimulant, nor saliva
secretion.
SUMMARY OF THE INVENTION
[0020] An object of the present invention is to provide a method
for treatment of external secretion disorders, especially the
method useful for treatment of at least one condition selected from
hypolacrimation, dry-eye syndrome, hyposalivation and dry-mouth
syndrome.
[0021] The present inventor found that at an amount as low as that
does not induce any conjunctival hyperemia, a fatty acid derivative
may improve hypolacrimation, improve basal tear secretion which is
not affected by a stimulant, and improve the dry-eye conditions. In
addition, the inventor also found that the fatty acid derivative
might also improve hyposalivation, and improve dry-mouth
conditions.
[0022] Therefore, the present invention provides a method for
treatment of external secretion disorders, especially, for
treatment of hypolacrimation, dry-eye syndrome, hyposalivation or
dry-mouth syndrome, which comprises administering an effective
amount of a fatty acid derivative to a subject in need of said
treatment.
[0023] According to this invention, the term "fatty acid" includes
not only the above mentioned linoleic acid,
di-homo-.gamma.-linolenic acid, arachidonic acid, .alpha.-linolenic
acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),
but also a compound comprising at least one carboxylic acid moiety
irrespective to presence or absence of double bonds, a cyclic group
or a substitute group, the number of the carbon atoms, position or
number of the double bonds, or a modification on the chain. In
addition, the fatty acid derivatives include not only the fatty
acids as above but also prostaglandin like compounds which include
PG.sub.S derived from said fatty acids, leukotriene like compounds,
thromboxanes, hydroxyeicosatetraenoic acids,
hydroperoxyeicosatetraenoic acids or their derivatives.
[0024] Furthermore, in the present invention, the fatty acid
derivatives also include the compound which have at least --COOH or
--CH.sub.2OH or the functional derivatives (salts, esters, ethers,
amides or the like) thereof at the terminal carbon atom,
irrespective to presence or absence of double bonds, a cyclic group
or a substitute group, the number of the carbon atoms, position or
number of the double bonds, or a modification on the chain.
[0025] According to the present invention, the term "prostaglandin
like compound" (hereinafter, referred as "PG like compound")
includes any of derivatives or substituted derivatives of a
compound having the prostanoic acid basic structure irrespective to
the configuration of the 5-memberd ring, number of double bonds in
the .alpha. or .omega. chain, presence or absence of hydroxy and
oxo groups or any other substituent, or any other modification.
Since the PG like compound of the present invention may have an
activity as an agonist for PG-receptor such as EP, FP, IP TP or DP
receptor, the "PG like compound" of the present invention may
include each compound having PG-receptor agonistic activity
irrespective to their structure.
[0026] The nomenclature of the PG like compounds used herein is
based on the numbering system of the prostanoic acid represented in
the above formula (A).
[0027] The formula (A) shows a basic skeleton of the C-20, but the
PG like compounds in the present invention are not limited to those
having the same number of carbon atoms. In the formula (A), the
numbering of the carbon atoms which constitute the basic skeleton
of the PG compounds starts at the carboxylic acid (numbered 1), and
carbon atoms in the .alpha.-chain are numbered 2 to 7 towards the
five-membered ring, those in the ring are 8 to 12, and those in the
.omega.-chain are 13 to 20. When the number of carbon atoms is
decreased in the a-chain, the number is deleted in the order
starting from position 2; and when the number of carbon atoms is
increased in the a-chain, compounds are named as substitution
compounds having respective substituents at position 2 in place of
carboxy group (C-1). Similarly, when the number of carbon atoms is
decreased in the .omega.-chain, the number is deleted in the order
starting from position 20; and when the number of carbon atoms is
increased in the .omega.-chain, the carbon atoms over position 20
are named as substituents. Stereochemistry of the compounds is the
same as that of the above formula (A) unless otherwise
specified.
[0028] In general, each of PGD, PGE and PGF represents a PG
compound having hydroxy groups at positions 9 and/or 11, but in the
present specification, they also include those having substituents
other than the hydroxy group at positions 9 and/or 11. Such
compounds are referred to as 9-dehydroxy-9-substituted-PG compounds
or 11-dehydroxy-11-substituted-PG compounds. A PG compound having
hydrogen in place of the hydroxy group is simply named as 9- or
11-dehydroxy compound.
[0029] As stated above, the nomenclature of the PG like compounds
is based on the prostanoic acid skeleton. However, in case the
compound has a similar partial construction as a prostaglandin, the
abbreviation of "PG" may be used. Thus, a PG compound of which
a-chain is extended by two carbon atoms; that is, having 9 carbon
atoms in the a-chain is named as 2-decarboxy-2-(2-carboxyethyl)-PG
compound. Similarly, a PG compound having 11 carbon atoms in the
.alpha.-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG
compound, and a PG compound having 10 carbon atoms in the
.omega.-chain is named as 20-ethyl-PG compound. These compounds,
however, may also be named according to the IUPAC
nomenclatures.
[0030] The PG like compounds used in the present invention may
include any of PG derivatives. Accordingly, for example, a PG.sub.1
compound having a double bond at 13-14 position and a hydroxy group
at 15-position, a PG.sub.2 compound having another double bond at
5-6 position, a PG.sub.3 compound having further double bond at
17-18 position, a 15-keto-PG compound having an oxo group in place
of the hydroxy group at the 15-position, a 15-dehydroxy-PG compound
having a hydrogen atom in place of the hydroxy group at the
15-position, or either 13,14-dihydro-PG compound wherein thedouble
bond at 13-14 position is single bond, or 13,14-didehydro-PG
compound wherein the double bond at the 13-14 position is triple
bond. Moreover, examples of substituted compounds and derivatives
include a compound wherein the terminal carboxyl group in the
.alpha.-chain of the above described compound is esterified, a
physiologically acceptable salt thereof, a compound wherein the
number of carbon atoms in the .alpha.- or .omega.-chain is
decreased or increased, a compound having side chains (e.g., 1 to 3
carbon atoms) on .alpha.- or .omega.-chains, a compound having
substituent(s) such as hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, and oxo, or double bond(s) on the
five-membered ring, a compound having substituent(s), such as
halogen, oxo, aryl and heterocyclic on the .alpha.-chain, a
compound having substituents such as halogen, oxo, hydroxy, lower
alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy,
aryl, aryloxy, heterocyclic and heterocyclic-oxy on the
.omega.-chain, and a compound having substituent such as lower
alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy,
aryl, aryloxy, heterocyclic and heterocyclic-oxy at the terminal of
the .omega.-chain of which is shorter than that of normal
prostanoic acid.
[0031] A preferred compound used in the present invention is
represented by the formula (I): 2
[0032] wherein W.sub.1, W.sub.2 and W.sub.3 are carbon or oxygen
atoms,
[0033] L, M and N are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a
group other than hydrogen, and the five-membered ring may have at
least one double bond;
[0034] A is --CH.sub.2OH, --COCH.sub.2OH, --COOH or its functional
derivative;
[0035] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2--, or --CH.sub.2--C.ident.C--;
[0036] Z is 3
[0037] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0038] R.sub.1 is a divalent saturated or unsaturated lower-medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted by halogen, oxo, hydroxy, lower alkyl, aryl or
heterocyclic; and
[0039] Ra is a saturated or unsaturated lower-medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted by
halogen, oxo, lower alkyl, hydroxy, lower alkoxy, lower
alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic or heterocyclic-oxy; cyclo(lower)alkyl;
cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic;
heterocyclic-oxy.
[0040] A group of particularly preferable compounds among the above
described compounds is represented by the general formula (II):
4
[0041] wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a
group other than hydrogen, and the five-membered ring may have at
least one double bond;
[0042] A is --CH.sub.2OH, --COCH.sub.2OH, --COOH or its functional
derivative;
[0043] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2--, or --CH.sub.2--C.dbd.C--;
[0044] Z is 5
[0045] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0046] X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen;
[0047] R.sub.1 is a divalent saturated or unsaturated lower-medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted by halogen, oxo, hydroxy, lower alkyl, aryl or
heterocyclic;
[0048] R.sub.2 is a single bond or lower alkylene; and
[0049] R.sub.3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl,
cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic or
heterocyclic-oxy.
[0050] Other preferred compound used in the present invention is
represented by the formula (III): 6
[0051] wherein Q.sub.1 and Q.sub.2 are hydrogen or lower alkyl, or
Q.sub.1 and Q.sub.2 are linked together to form
--(CH.sub.2).sub.n-- wherein n is 1, 2 or 0, and six-membered ring
may have at least one double bond;
[0052] A is --CH.sub.2OH, --COCH.sub.2OH, --COOH or its functional
derivative;
[0053] B is single bond, --CH.sub.2--CH.sub.2--, --CH.dbd.CH--,
--C.ident.C--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.dbd.CH--,
--C.ident.C--CH.sub.2--, or --CH.sub.2--C.ident.C--;
[0054] Z is 7
[0055] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0056] R.sub.1 is a divalent saturated or unsaturated lower-medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted by halogen, oxo, hydroxy, lower alkyl, aryl or
heterocyclic;
[0057] Ra is a saturated or unsaturated lower-medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted by
halogen, oxo, hydroxy, alkyl, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic or heterocyclic-oxy; cyclo(lower)alkyl;
cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic;
heterocyclic-oxy; and
[0058] the six-memberd ring may optionally have one or more double
bonds and may optionally consist a conjugated system.
[0059] Among the above described compound (III), a preferable
compound is benzene ring type compound in the six-membered
ring.
[0060] In the above formula, the term "unsaturated" in the
definitions for R.sub.1 and R.sub.a is intended to include at least
one or more double bonds and/or triple bonds that are isolatedly,
separately or serially present between carbon atoms of the main
and/or side chains. According to the usual nomenclature, an
unsaturated bond between two serial positions is represented by
denoting the lower number of the two positions, and an unsaturated
bond between two distal positions is represented by denoting both
of the positions. Preferred unsaturated bonds are a double bond at
position 2 and a double or triple bond at position 5.
[0061] The term "lower-medium aliphatic hydrocarbon" means a
hydrocarbon having a straight or branched chain of 1 to 14 carbon
atoms, wherein the side chain has preferably 1 to 3 carbon atoms.
The preferred R.sub.1 has 1 to 10, more preferably, 1 to 8 carbon
atoms, and the preferred Ra has 1 to 10, more preferably, 1 to 8
carbon atoms.
[0062] The term "halogen" includes fluorine, chlorine, bromine, and
iodine.
[0063] The term "lower" means a group having 1 to 6 carbon atoms
unless otherwise specified.
[0064] The term "lower alkyl" means a straight- or branched-chain
saturated hydrocarbon group having 1 to 6 carbon atoms, for
example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, and hexyl.
[0065] The term "lower alkoxy" means a lower alkyl-O-- wherein the
lower alkyl is as described above.
[0066] The term "hydroxy(lower)alkyl" means an alkyl as described
above, which is substituted by at least one hydroxy group, for
example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and
1-methyl-1-hydroxyethyl.
[0067] The term "lower alkanoyloxy" means a group represented by
the formula RCO--O--, wherein RCO-- is an acyl formed by oxidation
of a lower alkyl as described above, for example, acetyl.
[0068] The term "lower cycloalkyl" means a group formed by
cyclization of a lower alkyl group containing 3 or more carbon
atoms as described above, for example, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl.
[0069] The term "cyclo(lower)alkyloxy" means a group represented by
the formula cycloalkyl-O--, wherein cycloalkyl is described
above.
[0070] The term "aryl" includes aromatic hydrocarbon rings
(preferably monocyclic groups) which may be substituted, for
example, phenyl, tolyl and xylyl. Examples of the substituent in
this case include halogen, and halogen substituted lower alkyl
group, wherein halogen atom and lower alkyl group are as described
above.
[0071] The term "aryloxy" means a group represented by the formula
ArO--, wherein Ar is an aryl group as described above.
[0072] The term "heterocyclic" includes mono- to tri-cyclic,
preferably monocyclic heterocyclic group which is 5 to 14,
preferably 5 to 10 membered ring having optionally substituted
carbon atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom.
Examples of the heterocyclic group include furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazyl,
pyrimidyl, pyrazyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl,
imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino,
piperazinyl, morpholino, indolyl, benzothienyl, quinolyl,
isoquinolyl, puryl, quinazolinyl, carbazolyl, acridinyl,
phenanthridinyl, benzimidazolyl, benzimidazolonyl, benzothiazolyl,
phenothiazinyl. Examples of the substituent in this case include
halogen, and halogen substituted lower alkyl group, wherein halogen
atom and lower alkyl group are as described above.
[0073] The term "heterocyclic-oxy" means a group represented by the
formula HcO--, wherein Hc is a heterocyclic group as described
above.
[0074] The term "functional derivative" of A includes salts
(preferably pharmaceutically acceptable salts), ethers, esters, and
amides.
[0075] Examples of suitable "pharmaceutically acceptable salts"
include nontoxic salts which are commonly used, and salts with
inorganic bases, for example, alkali metal salts (sodium salt,
potassium salt and the like); alkaline earth metal salts (calcium
salt, magnesium salt and the like); ammonium salts; salts with
organic bases, for example, amine salts (such as methylamine salt,
dimethylamine salt, cyclohexylamine salt, benzylamine salt,
piperidine salt, ethylenediamine salt, ethanolamine salt,
diethanolamine salt, triethanolamine salt,
tris(hydroxymethylamino)- ethane salt, monomethyl-monoethanolamine
salt, lysine salt, procaine salt, and caffeine salt); basic amino
acid salts (such as arginine salt, and lysine salt); tetraalkyl
ammonium salts and the like. These salts may be manufactured from,
for example, corresponding acids and bases in accordance with a
conventional manner or salt exchange.
[0076] Examples of the ethers include alkyl ethers, for example,
lower alkyl ethers such as methyl ether, ethyl ether, propyl ether,
isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl
ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl
ethers such as octyl ether, diethylhexyl ether, lauryl ether and
cetyl ether; unsaturated ethers such as oleyl ether and linolenyl
ether; lower alkenyl ethers such as vinyl ether, allyl ether; lower
alkynyl ethers such as ethynyl ether and propynyl ether;
hydroxy(lower)alkyl ethers such as hydroxyethyl ether and
hydroxyisopropyl ether; lower alkoxy (lower)alkyl ethers such as
methoxymethyl ether and 1-methoxyethyl ether; optionally
substituted aryl ethers such as phenyl ether, tosyl ether,
t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and
benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzyl
ether, trityl ether and benzhydryl ether.
[0077] Examples of the esters include aliphatic esters, for
example, lower alkyl esters such as methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl
ester, pentyl ester, and 1-cyclopropylethyl ester; lower alkenyl
esters such as vinyl ester, and allyl ester; lower alkynyl esters
such as ethynyl ester, and propynyl ester; hydroxy(lower)alkyl
esters such as hydroxyethyl ester; and lower alkoxy(lower)alkyl
esters such as methoxymethyl ester, and 1-methoxyethyl ester as
well as, for example, optionally substituted aryl esters such as
phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester,
3,4-dimethoxyphenyl ester, and benzamidephenyl ester; and
aryl(lower)alkyl esters such as benzyl ester, trityl ester, and
benzhydryl ester. An example of amides includes mono- or di-lower
alkyl amides such as methylamide, ethylamide, and dimethylamide;
aryl amides such as anilide, and toluidide; and alkyl or aryl
sulfonyl amides such as methylsulfonyl amide, ethylsulfonyl amide,
and tolylsulfonyl amide.
[0078] Preferred examples of L and M include hydroxy and oxo, and
especially, M is hydroxy and L is oxo which provide a 5-membered
ring structure of, so called, PGE type.
[0079] Preferred examples of A-group include --COOH, and a
pharmaceutically acceptable salt, an ester and an amide
thereof.
[0080] In the formula (I) and (II), B is preferably
--CH.sub.2--CH.sub.2-- which provides the structure of so-called,
13,14-dihydro type.
[0081] In the formula (III), B is preferably single bond.
[0082] In the formula (I) and (II), Z is preferably .dbd.O which
provides the structure of so-called keto-type.
[0083] In the formula (III), Z is preferably hydroxy.
[0084] Preferred examples of X.sub.1 and X.sub.2 are that at least
one of them is halogen, more preferably, both of them are halogen,
especially, fluorine that provides a structure of, so called
16,16-difluoro type.
[0085] Preferred R.sub.1 is a hydrocarbon containing 2-10 carbon
atoms, more preferably, 4-8 carbon atoms.
[0086] Examples of R1 include, for example, the following
groups:
[0087] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0088] --CH.sub.2--CH.dbd.CH--CH.sub.2--,
[0089] --CH.sub.2--C.ident.C--CH.sub.2--,
[0090] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0091] --CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--,
[0092] --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--,
[0093]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0094] --CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
[0095] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--
[0096] --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--,
[0097] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)
--CH.sub.2--,
[0098]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.su-
b.2--CH.sub.2--,
[0099]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--,
[0100]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.db-
d.CH--,
[0101]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--,
[0102]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH-
.sub.3) --CH.sub.2--,
[0103] Preferred Ra is a hydrocarbon containing 1-10 carbon atoms,
more preferably, 1-8 carbon atoms and, especially, that having one
or two side chains with one carbon atom.
[0104] The configuration of the ring and the .alpha.- and/or
.omega. chains in the above formula (I) may be the same as or
different from that of the primary PGs. However, the present
invention also includes a mixture of a compound having a primary
type configuration and a compound of a non-primary type
configuration.
[0105] An example of the typical compound according to the present
invention is 13,14-dihydro-15-keto-16-mono or di-fluoro PGE
compound or a derivative thereof.
[0106] When a 15-keto-PG compound of the present invention has a
saturated bond between positions 13 and 14, the compound may be in
the keto-hemiacetal equilibrium by formation of a hemiacetal
between hydroxy at position 11 and keto at position 15.
[0107] If such tautomeric isomers as above are present, the
proportion of both tautomeric isomers varies with the structure of
the rest of the molecule or the kind of the substituent present.
Sometimes one isomer may predominantly be present in comparison
with the other. However, it is to be appreciated that the compounds
used in the invention include both isomers. Further, while the
compounds used in the invention may be represented by a structure
formula or name based on keto-type regardless of the presence or
absence of the isomers, it is to be noted that such structure or
name does not intend to eliminate the hemiacetal type compound.
[0108] In the present invention, any of isomers such as the
individual tautomeric isomers, the mixture thereof, or optical
isomers, the mixture thereof, a racemic mixture, and other steric
isomers may be used in the same purpose.
[0109] Some of the compounds used in the present invention may be
prepared by the method disclosed in EP-A 0281239 (corresponding to
JP-A 64-052753), EP-A 0284180 (corresponding to JP-A 01-104040),
EP-A 0289349 (corresponding to JP-A 01-151519), EP-A 0453127
(corresponding to JP-A 05-58992), EP-A 0690049 (corresponding to
JP-A 08-48665) or U.S. Pat. No. 5,369,127. The references as above
are herein incorporated by reference. Alternatively, these
compounds may be prepared by a process analogous to that described
herein or by any process known in the art.
[0110] As mentioned above, one of the characteristics of the PG
like compounds of the present invention is a PG-receptor (ex. EP,
FP, IP, TP and DP-receptor) agonist activity. Accordingly, the PG
like compounds used in the present invention include any of
compounds having a PG-receptor agonist activity, irrespective to
their structure.
[0111] The above described fatty acid derivatives of the present
invention are effective in treating external secretion disorders,
especially in treating hypolacrimation including disorders in basal
tear secretion, as well as in improving and treating of dry-eye
conditions (i.e. decreased lacrimal fluid secretion and
accompanying corneal disorders). Further, said compounds are also
effective in improving hyposalivation, as well as in improving and
treating of dry-mouth conditions. Therefore, the composition is
useful for treatment of external secretion disorders, especially
hypolacrimation including disorders in basal tear secretion and/or
dry eye condition, or hyposalivation and/or dry-mouth
conditions.
[0112] The term "treatment" or "treating" used herein refers to any
means of control of a condition of a subject including prevention,
cure, relief of the condition, and arrestation or relief of
development of the condition.
[0113] The subjects who are intended to be treated by the method of
the present invention are those suffered from external secretion
disorder including xerosises such as dry-eye syndrome
(xerophthalmia), dry-mouth syndrome (xerostomia), dry-nose syndrome
(xeromycteria), dry-skin syndrome (xeroderma), dry-vagina syndrome
(symptom of vaginal dryness); chronic pancreatitis, chronic
gastritis, and chronic bronchitis due to the depression of external
secretion. Especially, those with conditions which are likely to
induce dry-eye syndrome include hypolacrimation, alacrima,
xerophtalmia, Sjogren's syndrome, dry keratoconjunctivitis,
Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis,
diabetes, post cataract operation and allergic conjunctivitis. In
addition, those with dry-eye syndrome, which may be induced by
aging, long term VDT operation, dryness of an air-conditioned
room.
[0114] Systemic factors which may cause dry-mouth syndrome includes
febrile disease, hypohydremia, endcrinopathy (myxedema, Basedow's
disease, diabetes insipidus, etc.), metabolic disorders (diabetes,
uremia, liver cirrhosis, etc.), deficiency of vitamin A or B,
autoimmune diseases (Sjogren's syndrome, progressive scleroderma,
etc.), anemia, bleeding, aging, various medications (sedatives,
parasympatholytic drugs, antihistamines, etc.). In addition,
topical factors may include sialadenitis, atrophy of salivary
gland, sequela of radiotherapy, malformation ecodermal dysplasia,
etc) and so forth.
[0115] The external secretion disorders means a state where
abnormal external secretion (i.e. decrease or stop of the
secretion), which may be caused by any etiology, is observed,
especially the state with abnormal lacrimal fluid secretion
including basal tear secretion, and abnormal salivation.
[0116] The method of the present invention may be effectuated by
administering a composition comprising a fatty acid derivative as
an active ingredient to the subject either orally or parenterally.
The dosage form of the composition may be eye drops, ophthalmic
ointment, sublingual tablets, troches, chewable tablets,
collutoriums, sprays, ointments, powders, granules, tablets,
capsules, suppository and vaginal suppository. Dosage forms for
topical application, such as eyedrops, ophthalmic ointment,
sublingual tablets and ointment are preferable. These dosage forms
may be prepared according to any of conventional methods.
[0117] The composition used in the present invention may be admixed
with an appropriate pharmaceutically acceptable additive. The
additive is a compound which may be used together with the
unsaturated fatty acid derivative of the invention and may include
excipient, diluent, filler, solvent, lubricant, adjuvant, binder
disintegrator, coating agent, cupsulating agent, ointment base,
suppository base, aerosol base, emulsifier, dispersant, suspensing
agent, thickener, isotonic agent, buffering agent, analgesia,
preservative, anti oxidant, corrigent, flavor, colorant, and
functional agent (for example, cyclodextrin and biodegradable
polymer). The additive may be selected based on any of reference
books on pharmaceuticals.
[0118] The composition used in the present invention may further be
admixed with any of pharmaceutically active agents in so far as
said agent is compatible with the purpose of the present
invention.
[0119] In the present invention, the "effective amount" of a fatty
acid derivative may vary depending on the kind of the fatty acid
used, the condition to be treated, age and body weight of the
patient, dosage form, duration of the treatment, desired
therapeutic effect and so on. For example, when the composition to
be used in the treatment is formulated as eyedrops, a dosage form
containing 0.000001-10.0 wt %, preferably 0.00001-1.0 wt % of the
fatty acid derivative may be administered several drops per one
eye, preferably 1-4 drops, several times per day, preferably, 1-6
times per day. When it is formulated as a sublingual tablet, a
dosage form containing 0.000001-10.0 wt %, preferably 0.00001-1.0
wt % of the fatty acid derivative may be administered in the oral
cavity several times, preferably 1-6 times per day. Further, when
it is formulated as. an ointment, topical administration of a
dosage form containing 0.000001-10.0 wt %, preferably 0.00001-1.0
wt % of the fatty acid derivative for several times, preferably,
1-6 times per day may provide an enough effect.
EXAMPLES
[0120] The present invention will be illustrated in more detail by
way of the following examples. These examples should not be used as
any limitation of the present invention.
Test Example 1
Effect on Whole Tear Secretion of Normal Rabbits
[0121] (1) Test Animals
[0122] Male Japanese albino rabbits (Std:JW/CSK) were used.
[0123] (2) Method of Administration
[0124] Ophthalmic solution comprising 0.001% of
13,14-dihydro-15-keto-16,1- 6-difluoro-PGE.sub.1 as an active
ingredient of the present invention was prepared and used as a test
composition. As a control, the vehicle of said solution without the
active ingredient was used.
[0125] Each of the compositions was instilled singly to eight eyes
at the amount of 30 .mu.l/eye. After the administration, the time
course of the tear secretion change was examined according to the
following method.
[0126] (3) Examination
[0127] Whole Tear Secretion
[0128] Before (0 hour) and 0.5, 2, 4, and 6 hours after the
instillation, the whole tear secretion was determined.
[0129] Under no anesthetization, one edge of the Schirmer's test
strip (Showa Yakuhin Kako Co., Ltd., Lot No. 70080) was inserted
into the conjunctival sac of the each test animal. One minute
after, the strip was removed and the length of the moisted part was
read from the scale provided on the strip to determine the amount
of whole tear secretion.
[0130] (4) Result
[0131] The result of the whole tear secretion test is shown in the
Table 1. No stimulating response, such as rubor in the front of the
eye was observed after the administration in both of the test
animals and the control animals.
[0132] These data are shown simultaneously with the statistical
analysis.
1 TABLE 1 number of the whole tear eyes tested time (hr) secretion
(mm/min.) Control 8 before the 5.5 .+-. 0.3 group administration 8
0.5 8.1 .+-. 0.7 8 2 8.3 .+-. 0.8 8 4 7.3 .+-. 0.7 8 6 7.1 .+-. 0.7
test 8 before the 5.3 .+-. 0.2 group administration 0.001% 8 0.5
17.0 .+-. 0.5.sup.## 8 2 14.1 .+-. 0.5.sup.## 8 4 11.7 .+-.
0.6.sup.## 8 6 10.5 .+-. 1.0.sup.# .sup.#p < 0.05 .sup.##p <
0.01: comparison with the value at the corresponding time of the
control group (Student's-t test).
[0133] According to the above result, the test group comprising the
compound of the present invention as an active ingredient caused a
significant increase of the amount of whole tear secretion at a
dose which does not induce any stimulating response such as rubor
in the front of the eye. Therefore, the compound of the present
invention was revealed to have an activity to increase the amount
of tear secretion without any stimulating response.
Test Example 2
Effect of the Compound on Decreased Whole Tear Secretion, Decreased
Basal Tear Secretion and Keratoepithelial Lesion in Rabbit Dry-Eye
Syndrome Model, Which was Induced by Trigeminal Denervation
[0134] (1) Test Animals
[0135] Fifteen male Japanese albino rabbits (Std:JW/CSK) were
used.
[0136] (2) Generating Rabbit Dry-Eye Syndrome Model by Trigeminal
Denervation.
[0137] i) Operational Procedure
[0138] Urethane (ALDRICH) was administered i.p. at the dose of 1
g/kg to the rabbits of which occipital hair had been shaved.
[0139] After disinfection of the shaved area, midline incision of
the skin was made from the frontal bone to the ear root, and the
muscular tissue around the periosteum, temporal bone and
manidibular articular process were detached. After the detachment,
a hole of 2.times.1.5 cm in size was made in the bone from the
parietal medial region to the temporal region by means of the bone
drill (URAWA KOGYO Co., Ltd. MINITOR C-130) under the surgical
microscope (KONAN CAMERA R&I Inc., PMO-50). Then, the dura was
detached from the cranial bone while cotton bud was kept inserted
between the temporal bone and the dura. After the detachment was
made up to the cranial base, detachment was further made toward the
medial border of the petrous part of temporal bone in the carnial
cavity, to find the trigeminal nerve in the petrous part. Then, the
dura of about 1 to 2 mm on the nasal side of the semilunar ganglion
was incised. After the incision, the two branches of nerve
fascicle, i.e. the first branch (ocular nerve) of the trigeminal
nerve and the second branch (maxillary nerve) were pulled laterally
and cut with corneoscleral scissors. Immediately after the
operation, miosis of the ipsilateral eye was confirmed and then the
cotton kept inserted was removed, and the skin at the head was
closed with suture. After the operation, an antibiotic (MYCILLIN
SOL.RTM. Meiji) was administered i.m. at the dose of 0.1 ml/kg.
[0140] The trigeminal denervation was made only on the left eye
side, while on the right eye side, no trigeminal denervation nor
sham operation was made.
[0141] After the operation, animals in stable state and showed
decreased whole tear secretion, decreased basal tear secretion, and
keratoepithelial lesion were subjected to the following test.
[0142] (3)Method of Administration.
[0143] 13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1 was used as
an active ingredient of the present invention to prepare test
eyedrops containing 0.0001% and 0.001% of the compound. As a
control, the vehicle of the eyedrops without the active ingredient
was used.
[0144] Each of the compositions was instilled to the eyes everyday
at the volume of 30 .mu.l/eye two times a day (at 10:00 and 18:00)
for two weeks. Five eyes per each of the test groups and the
control group were treated and then examined for the whole tear
secretion, the basal tear secretion and the keratoepithelial lesion
as follows.
[0145] (4) Examination
[0146] i) Whole Tear Secretion (Schirmer's Test)
[0147] Before the start of the instillation (week 0), and 1, 2, and
3 weeks after the start, the whole tear secretion was measured two
hours after the first instillation on the day of examination.
[0148] Under no anesthetization, one edge of the Schirmer's test
strip (Showa Yakuhin Kako Co., Ltd., Lot No. 70080) was inserted
into the conjunctival sac of each test animal. One minute after,
the strip was removed and the length of the moistened part was read
from the scale provided on the strip to determine the amount of
whole tear secretion.
[0149] ii) Basal Tear Secretion
[0150] Before the start of the instillation (week 0), and 1, 2, and
3 weeks after the start, the basal tear secretion was measured 2
hours after the 1st instillation on the day of the examination.
[0151] Keratoconjunctiva was anesthetized by instillation of 4%
lidocaine (Xylocaine.RTM. 4% for ophthalmic solution; Fujisawa
Pharmaceutical Co., Ltd.), the eye drops and the tear around the
eyelid were wiped off about 5 minutes after and loss of
keratoconjunctival esthesia was confirmed with the Cochet-Bonnet
type esthesiometer. Then, one edge of the Shirmer's test strip was
inserted into the conjunctival sac and kept there for 5 minutes.
The length of the moistened part was read from the scale on the
strip.
[0152] The basal tear secretion was expressed by mean value per
minute calculated from the 4-minutes value obtained by subtracting
the initial 1-minute value from the 5-minutes Sirmer's test, so
that the spontaneous volume of the tear retained in the
conjunctival sac might be excluded.
[0153] iii) Keratoepithelial Lesion
[0154] Before the start of instillation (week 0) and 1,2, and 3
weeks after the start, the keratoepithelial lesion was evaluated
two hours after the first instillation on the day of
examination.
[0155] Each animal was placed in a stainless steel fixator, and
given instillation of 50 .mu.l of the mixture of 1% rose bengal and
1% fluorescein to stain their keratoconjunctival epithelium.
Stained area, i.e. the abnormal area on the epithelium was
evaluated according to the criteria shown in the Table 2.
2TABLE 2 Scores Stained area of the keratoconjunctiva 0 None 0.5
only a part was stained slightly 1 the area was less than 1/4 2 the
area was more than 1/4 and less than 1/2 3 the area was more than
1/2 and less than 3/4 4 the area was more than 3/4
[0156] (5) Results
[0157] The result of the whole tear secretion is shown in the Table
3, that of the basal tear secretion is shown in the Table 4, and
that of the keratoepithelial lesion is shown in the Table 5.
Statistical analysis is also shown with the data.
3 TABLE 3 whole tear number time secretion of eyes (weeks)
(mm/min.) before the 15 -- 5.23 .+-. 0.33 operation after the 15 --
3.10 .+-. 0.28** operation control 5 before 3.10 .+-. 0.40** group
administration 5 1 4.40 .+-. 1.21 5 2 3.80 .+-. 0.64* 5 3 3.90 .+-.
0.90 test group 5 before 3.00 .+-. 0.61** 0.0001% administration 5
1 7.10 .+-. 0.51**.sup.++ 5 2 6.60 .+-. 0.37*.sup.##++ 5 3 6.30
.+-. 0.68.sup.++ test group 5 before 3.20 .+-. 0.51** 0.001%
administration 5 1 11.20 .+-. 0.51**.sup.##++ 5 2 10.50 .+-.
0.57**.sup.##++ 5 3 9.90 .+-. 0.81**.sup.##++ *p < 0.05 **p <
0.01: comparison with the value before the operation (student's-t
test) .sup.+p < 0.05 .sup.++p < 0.01: comparison with the
value at the corresponding time in the control group (Student's
t-test) .sup.#p < 0.05 .sup.##p < 0.01: comparison with the
value of time 0 (before administration) in each treatment
group.
[0158]
4 TABLE 4 basal tear number time secretion of eyes (weeks)
(mm/min.) before the 15 -- 1.45 .+-. 0.10 operation after the 15 --
0.43 .+-. 0.05.sup.[**.sup.] operation control 5 before 0.43 .+-.
0.10** group administration 5 1 0.88 .+-. 0.21* 5 2 0.73 .+-.
0.22** 5 3 0.73 .+-. 0.18** test group 5 before 0.43 .+-.
0.06.sup.[**.sup.] 0.0001% administration 5 1 1.53 .+-.
0.26.sup.[+] 5 2 1.60 .+-. 0.11**.sup.++ 5 3 1.48 .+-.
0.17.sup.#[++] test group 5 before 0.43 .+-. 0.08** 0.001%
administration 5 1 2.00 .+-. 0.12*.sup.##++ 5 2 2.00 .+-.
0.18*.sup.##++ 5 3 2.00 .+-. 0.14*.sup.##++ .sup.[**.sup.]p <
0.01: comparison with the value before the operation (Aspin-Welch
test) *p < 0.05 **p < 0.01: comparison with the value before
the operation in each group (student's-t test) .sup.++p < 0.01:
comparison with the value at the corresponding time in the control
group (Student's t-test) .sup.[+]p < 0.05 .sup.[++]p < 0.01:
comparison with the value at the corresponding time in the control
group (Aspin-Welch test) .sup.#p < 0.05 .sup.##p < 0.01:
comparison with the value of time 0 (before administration) in each
test group (Student's-t test).
[0159]
5 TABLE 5 number of time Keratoepithelial eyes (weeks) lesion
(score) before the 15 -- 0.07 .+-. 0.05 operation after the 15 --
2.93 .+-. 0.15.sup.[**.sup.] operation control 5 before 2.80 .+-.
0.20.sup.[**.sup.] group administration 5 1 1.90 .+-.
0.51.sup.[**.sup.] 5 2 1.60 .+-. 0.58.sup.[**.sup.] 5 3 1.50 .+-.
0.32.sup.[**.sup.]++ test group 5 before 3.00 .+-.
0.32.sup.[**.sup.] 0.0001% administration 5 1 1.00 .+-.
0.27.sup.[*.sup.]++ 5 2 0.50 .+-. 0.16.sup.[*.sup.]++ 5 3 0.40 .+-.
0.19.sup.#++ test group 5 before 3.00 .+-. 0.32.sup.[**.sup.]
0.001% administration 5 1 0.70 .+-. 0.34.sup.++ 5 2 0.10 .+-.
0.10.sup.[++] 5 3 0.10 .+-. 0.10.sup.[##][++] .sup.[*.sup.]p <
0.05 .sup.[**.sup.]p < 0.01: comparison with the value before
the operation (Aspin-Welch test) .sup.++p < 0.01: comparison
with the value before the operation in each group (student's-t
test) .sup.[++]p < 0.01: comparison with the value at the
corresponding time in the control group (Aspin-Welch test)
.sup.[##]p < 0.01: comparison with the value of time 0 (before
administration) in each test group (Aspin-Welch test).
[0160] Based on the above results, the test group comprising the
compound of the present invention as an active ingredient improved
the decreased whole tear secretion and basal tear secretion as well
as keratoconjunctival lesion accompanied by the decrease of the
tear secretion observed in the dry-eye syndrome model animals.
Therefore, the composition of the present invention is appear to be
useful for treatment of hypolacrimation including disorders in
basal tear secretion as well as dry-eye conditions i.e.
hypolacrimation and accompanying keratoconjunctival lesion.
Test Example 3
Exaltation of Salivation
[0161] The effect of the composition of the present invention on
salivary secretion was determined.
[0162] (1) Test Animals
[0163] Male and female rats (Crj:CD strain) were used. Each of the
test and control groups contains 16 animals.
[0164] (2) Method of Administration
[0165] 13,14-dihydro-15-keto-16,16-difuloro-PGE.sub.1 was used as
an active ingredient of the present invention to prepare test
solution containing 0.2 mg/ml of the compound.
[0166] 5 ml/kg of the solution (1 mg/kg of the compound) was
forcedly administrated orally once a day. For the animals of
control group, 5 ml/kg of the vehicle without the active ingredient
was administrated once a day. The administration was continued for
four weeks.
[0167] (3) Examination
[0168] The amount of the saliva of the test group and control group
was evaluated visually everyday. (4) Result In the group of the
animals administered with the fatty acid derivative of the present
invention, exaltation of saliva was observed in 8 of 16 rats on the
10th day after the start of the administration, and after that, the
number of the rats with salivary exaltation was increased time
dependently. Subsequent to the 22nd day after the start, each of 16
rats administrated with the composition showed salivary exaltation.
Whereas, in the control group, all animals kept the normal salivary
secretion over the whole administration term.
Test Example 4
Exaltation of Salivation
[0169] The effect of the composition of the present invention on
salivary secretion was determined.
[0170] (1) Test Animals
[0171] Male rats(SD strain) were used.
[0172] Each of the test and control groups contains 8 animals.
[0173] (2) Method of Administration
[0174] 13,14-dihydro-15-keto-16,16-difuloro-PGE.sub.1 was used as
an active ingredient of the present invention to prepare test
solution containing 0.2 mg/ml of the compound.
[0175] 5 ml/kg of the solution (1.0 mg/kg of the compound) was
forcedly administrated orally once a day. For the animals f control
group, 5 ml/kg of vehicle without the active ingredient was
administrated once a day. The administration was continued for 10
days.
[0176] (3) Examination
[0177] The amount of the saliva of the test group and control group
was measured one hour after the administration on 10th day. The
edge of a paper filter(Schirmer's test strip, Showa Yakuhin Kako
Co., Ltd.) was inserted between lower gingiva and mandibula. Three
minutes after, the paper filter was removed and the weight of the
saliva was calculated by the following formula.
weight of saliva=(the weight of paper filter including
saliva)-(weight of only paper filter)
[0178] (4) Result
[0179] The result of the salivary secretion is shown in the table
6.
6 TABLE 6 Number of Salivary weight animals (mg, mean .+-. S.E.)
Control 8 4.6 .+-. 0.9 group Test group 8 18.1 .+-. 5.6* *P <
0.05, compared with control group (U-test of Mann-Whitney)
[0180] In the group of the animals administered with the fatty acid
derivative of the present invention, salivary secretion was
significantly increased compared with that of the control
group.
Test Example 5
Effect on Whole Tear Secretion of Normal Rabbits
[0181] (1) Test Animals
[0182] Male Japanese albino rabbits were used.
[0183] (2) Method of Administration
[0184] Ophthalmic solution comprising an active ingredient of the
present invention was prepared and used as a test composition.
[0185] Each of the compositions was instilled to the eye singly at
the amount of 30 .mu.l/eye.
[0186] (3) Examination
[0187] Amount of the Tear Secretion
[0188] Before (0 hour) and 2 hours after the instillation, the
whole tear secretion was determined.
[0189] Under no anesthetization, one edge of the Schirmer's test
strip (Showa Yakuhin Kako Co., Ltd.) was inserted into the
conjunctival sac of the each test animal. One minute after, the
strip was removed and the length of the moisted part was read from
the scale provided on the strip to determine the amount of whole
tear secretion.
[0190] The rate (%) of increased amount of whole tear secretion was
calculated at the 2 hours after the instillation compared with the
before(0 hour).
[0191] (4) Result
[0192] The result of the whole tear secretion test is shown in the
Table 7. In addition to the data in the table, no stimulating
response, such as rubor, in the front of the eye was observed after
the administration of test compounds.
7TABLE 7 Concentration Number of Rate of the increased Test of the
test the eyes whole tear secretion compound compound tested (%)
Compound 1 30 .mu.g/g 4 40.7 Compound 2 10 .mu.g/g 4 52.5 Compound
3 10 .mu.g/g 4 52.0 Compound 4 3 .mu.g/g 4 61.8 Compound 5 3
.mu.g/g 4 43.5 Compound 6 100 .mu.g/g 4 44.0 Compound 7 2000
.mu.g/g 4 56.9 Compound 8 1 .mu.g/g 4 24.8 Compound 1:
15-dehydroxy-13,14-dihydro-14,15-dehydro-16-keto-17,17-difluoro-PGE.sub.1-
-methyl ester Compound 2: 13,14-dihydro-15-keto-16,16-difluoro-20--
ethyl-PGE.sub.1 Compound 3: 2-decarboxy-2-(2-carboxyethyl)-13,14-d-
ihydro-15-keto-16,16-difluoro- PGE.sub.1 Compound 4:
13,14-dihydro-15-keto-16,16-difluoro-PG.sub.2.alpha.-methyl ester
Compound 5:
11-dehydroxy-13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1
Compound 6: 13,14-dihydro-15-keto- PGE.sub.1 Compound 7:
2-decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,16-difluoro-20-et-
hyl-PGE.sub.1-isopropyl ester Compound 8: 13,14-dihydro-15-keto-16-
,16-difluoro-PGE.sub.2
* * * * *