U.S. patent application number 10/133450 was filed with the patent office on 2002-10-31 for ophthalmic composition.
This patent application is currently assigned to R-TECH UENO, LTD.. Invention is credited to Kato, Ichie, Ueno, Ryuji.
Application Number | 20020161015 10/133450 |
Document ID | / |
Family ID | 12010371 |
Filed Date | 2002-10-31 |
United States Patent
Application |
20020161015 |
Kind Code |
A1 |
Ueno, Ryuji ; et
al. |
October 31, 2002 |
Ophthalmic composition
Abstract
The ophthalmic composition of this invention are used for
treatment of diabetic corneal lesion and/or for treatment of
deteriorated corneal esthesia, which comprises, as an active
ingredient, a compound represented by the general formula (I): 1
wherein A and B are independently lower alkylene, X, Y, and Z are
independently halogen, or a pharmacologically acceptable salt
thereof. In addition, the ophthalmic composition of this invention
are used for treatment of non-diabetic corneal lesion, for
treatment of dry eye syndrome, and/or for treatment of
hypolacrimation which comprises, as an active ingredient, an aldose
reductase inhibitor. The ophthalmic compositions of this invention
are effective for treatment of at least one disease selected among
corneal lesion, deteriorated corneal esthesia, dry eye syndrome,
and hypolacrimation.
Inventors: |
Ueno, Ryuji; (Montgomery,
MD) ; Kato, Ichie; (Kawanishi-shi, JP) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 Pennsylvania Avenue, NW
Washington
DC
20037-3213
US
|
Assignee: |
R-TECH UENO, LTD.
|
Family ID: |
12010371 |
Appl. No.: |
10/133450 |
Filed: |
April 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10133450 |
Apr 29, 2002 |
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09485414 |
Aug 3, 2000 |
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6403598 |
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09485414 |
Aug 3, 2000 |
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PCT/JP99/00369 |
Jan 29, 1999 |
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Current U.S.
Class: |
514/266.3 |
Current CPC
Class: |
A61K 31/00 20130101;
A61P 27/02 20180101; Y10S 514/912 20130101; A61K 31/517
20130101 |
Class at
Publication: |
514/266.3 |
International
Class: |
A61K 031/517 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 30, 1998 |
JP |
10-19836(PAT.) |
Claims
1. An ophthalmic composition for treatment of diabetic corneal
lesion and/or for treatment of deteriorated corneal esthesia which
comprises, as an active ingredient, a compound represented by the
general formula (I): 8wherein A and B are independently lower
alkylene, X, Y, and Z are independently halogen, or a
pharmacologically acceptable salt thereof.
2. The ophthalmic composition of claim 1, wherein A and B are
independently methylene, X is chlorine, Y is bromine, and Z is
fluorine.
3. The ophthalmic composition of claim 1 or claim 2 that is used
for treatment of diabetic corneal lesion.
4. The ophthalmic composition of claim 1 or claim 2 that is used
for treatment of deteriorated corneal esthesia.
5. The ophthalmic composition of any of claims 1 to 4 that is in
the form of preparation for eye local administration.
6. An ophthalmic composition for treatment of non-diabetic corneal
lesion which comprises, as an active ingredient, an aldose
reductase inhibitor.
7. An ophthalmic composition for treatment of dry eye syndrome
which comprises, as an active ingredient, an aldose reductase
inhibitor.
8. An ophthalmic composition for treatment of hypolacrimation which
comprises, as an active ingredient, an aldose reductase
inhibitor.
9. The ophthalmic composition of any of claims 6 to 8, wherein said
aldose reductase inhibitor is a compound represented by the general
formula (I): 9wherein A and B are independently lower alkylene, X,
Y, and Z are independently halogen, or a pharmacologically
acceptable salt thereof.
10. The ophthalmic composition of claim 9, wherein A and B are
methylene, X is chlorine, Y is bromine, and Z is fluorine.
11. The ophthalmic composition of any of claims 6 to 10 which is in
the form of preparation for eye local administration.
12. A method for treating diabetic corneal lesion and/or
deteriorated corneal esthesia which comprises administering an
effective amount of a compound represented by the general formula
(I): 10wherein A and B are independently lower alkylene, and X, Y,
and Z are independently halogen, or a pharmacologically acceptable
salt thereof, to a subject in need of a treatment of diabetic
corneal lesion and/or deteriorated corneal esthesia.
13. A method for treating non-diabetic corneal lesion which
comprises administering an effective amount of an aldose reductase
inhibitor to a subject in need of a treatment of non-diabetic
corneal lesion.
14. A method for treating dry eye syndrome which comprises
administering an effective amount of an aldose reductase inhibitor
to a subject in need of a treatment of dry eye syndrome.
15. A method for treating hypolacrimation which comprises
administering an effective amount of an aldose reductase inhibitor
to a subject in need of a treatment of hypolacrimation.
16. Use of a compound represented by the general formula (I):
11wherein A and B are independently lower alkylene, and X, Y, and Z
are independently halogen, or a pharmacologically acceptable salt
thereof, in the manufacture of an ophthalmic composition for the
treatment of diabetic corneal lesion and/or deteriorated corneal
esthesia.
17. Use of an aldose reductase inhibitor in the manufacture of an
ophthalmic composition for the treatment of non-diabetic corneal
lesion.
18. Use of an aldose reductase inhibitor in the manufacture of an
ophthalmic composition for the treatment of dry eye syndrome.
19. Use of an aldose reductase inhibitor in the manufacture of an
ophthalmic composition for the treatment of hypolacrimation.
Description
TECHNICAL FIELD
[0001] This invention relates to ophthalmic compositions, in
particular, those for treatment of corneal lesions, those for
treatment of deteriorated corneal esthesia, those for treatment of
dry eye syndrome, and those for treatment of hypolacrimation.
PRIOR ART
[0002] Corneal lesions are caused by defects in the corneal tissue.
Defects in the epithelium generally give rise to subjective
symptoms including foreign body sensation, eye pain, photophobia,
tear secretion, etc. Defects in the corneal tissue are called
epithalaxia or erosion when they are restricted only in the
epithelium, and corneal ulcer when they extend from the Bowman's
membrane to the parenchyma.
[0003] There are various possible factors involved in corneal
lesions, including pathological factors such as diabetes,
inflammation, allergy, microorganisms (virus, bacteria, fungi,
etc.) etc., chemical factors such as cytotoxicity by chemicals,
caustic effect by acids or alkalis, etc., and physical factors such
as dryness (dry eye syndrome, etc.) and trauma due to foreign
bodies (contact lens, etc.), burn, etc. It has recently been
reported that antiseptics contained in eye drops such as
benzalkonium chloride and chlorobutanol, antibiotics of the
aminoglycoside series, non-steroidal antiphlogistics, IDU,
pimaricin, etc. impair the corneal epithelium.
[0004] Various treatments have been attempted depending on the site
affected and the severity of the corneal lesion. In addition to
physical treatments such as instillation of antibiotic-containing
ointment plus pressure eye-patch treatment, use of therapeutic soft
contact lens, and corneal superficial puncture, instillation of
fibronectin, hyaluronic acid, or a high osmotic agent is currently
employed. From the viewpoint of treatment of diabetic
complications, it has been reported that aldose reductase
inhibitors are effective in treatment of diabetic corneal lesions
However, for example in cases where the symptoms have become
aggravated so that the keratoepithelium becomes detached from the
corneal parenchyma, satisfactory recovery cannot be attained at
present with any of the treatments described above. Thus the
treatments desired are those effective even in considerably
progressive corneal lesions where the epithelium has been detached
or defected.
[0005] The cornea is one of the most sensitive tissues on the body
surface, and sensory nerve endings are distributed all over the
cornea. Therefore when the corneal esthesia remains normal, the
patient can notice the pain due to pathological conditions or
lesions in cornea. When the corneal esthesia is deteriorated,
however, no subjective symptoms are noticed and this promotes to
further aggravation of the corneal lesions.
[0006] Factors that are known to deteriorate corneal esthesia
include aging, diseases (corneal herpes, diabetes, etc.), use of
contact lens, and ophthalmologic surgery (surgery for cataract,
corneal transplantation, surgery for retinal detachment, etc.). Not
only for treatment but also for prevention of progress of the
pathological conditions, treatments that may normalize the
subjective symptoms of the patients, i.e. agents that may improve
the deteriorated corneal esthesia due to various diseases are being
desired.
[0007] One of the opthalmologic symptoms that became lately the
center of wide interest is dry eye syndrome. Dry eye syndrome is
defined as "the condition where the tear quantity has been
decreased or tear quality has become abnormal, irrespective of
whether the keratoconjunctival lesion is present or absent"
(Yamada, N., et al., Folia Ophthalmol. Jpn., 43, 1289-1293 (1992)),
including dry eye syndrome noted in diseases such as
hypolacrimation, alacrima, xerophthalmia, Sjogren's syndrome, dry
keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid,
marginal blepharitis, diabetes, etc. dry eye syndrome noted after
surgery for cataract, or accompanied with allergic conjunctivitis,
etc., and dry, eye syndrome observed in hypolacrimation due to
increased VDT (visual display terminal) tasks or dry air in an
air-conditioned room.
[0008] There are various causes of dry eye syndrome some of which
remain unidentified. Dry eye syndrome is treated only by
administration of artificial tears for increase of the quantity of
tear retained within the conjunctival sac to relieve the subjective
symptoms, or by prevention of eyes from drying. It has been desired
that substances capable of bringing about satisfactory treatment
including improvement of hypolacrimation are provided.
[0009] Tear secretion is classified into basal tear secretion and
reflex tear secretion. Basal tear secretion means tear secretion
under ordinary conditions with the eyelid open, being considered to
be mainly from the accessory lacrimal glands (Krause gland,
Wolfring gland, etc.). On the other hand, reflex tear secretion
means tear secretion in the presence of some stimulation to the
keratoconjunctival surface, nasal mucosa, etc. or accompanied with
mental changes such as grief and joy. It is considered to be from
the main lacrimal gland. Therefore improvement of decreased basal
tear secretion, i.e. tear secretion under ordinary conditions with
the eyelid open, is particularly important as judged from the
symptoms of dry eye syndrome.
DISCLOSURE OF THE INVENTION
[0010] This invention intends to solve the problems described
above, and one of the objectives is to provide ophthalmic
compositions effective in treatment of at least one disease
selected among corneal lesion, deteriorated corneal esthesia, dry
eye syndrome, and hypolacrimation.
[0011] The inventors have eventually found as the result of their
researches that the compounds represented by the general formula
(I): 2
[0012] wherein, A and B are independently lower alkylene, and X, Y,
and Z are independently halogen, are excellent improvement of
diabetic corneal lesion and deteriorated corneal esthesia.
[0013] The inventors have also found that the compounds capable of
inhibiting aldose reductase including the compounds represented by
the above-mentioned general formula (I) are excellent in
improvement not only of diabetic corneal lesion but also of
non-diabetic corneal lesions, and that the compounds are excellent
in improvement of dry eye syndrome, especially hypolacrimation
including diminished basal tear secretion. Thus, they completed
this invention.
[0014] The invention is explained in detail in the following.
[0015] (1) An ophthalmic composition for treatment of diabetic
corneal lesion and/or for treatment of deteriorated corneal
esthesia of which comprises, as an active ingredient, a compound
represented by the general formula (I): 3
[0016] wherein, A and B are independently lower alkylene and X, Y,
and Z are independently halogen (named the compound hereinafter),
or a pharmacologically acceptable salt thereof.
[0017] (2) The ophthalmic composition described in (1) wherein in
the general formula (I) A and B are independently methylene, X is
chlorine, Y is bromine, and Z is fluorine atom.
[0018] (3) The ophthalmic composition described in (1) or (2) that
are used for treatment of diabetic corneal lesion.
[0019] (4) The ophthalmic composition described in (1) or (2) that
are used for treatment of deteriorated corneal esthesia.
[0020] (5) The ophthalmic composition described in any of (1) to
(4) that are in the form of preparations for eye local
administration.
[0021] (6) An ophthalmic composition for treatment of non-diabetic
corneal lesions which comprises, as an active ingredient, an aldose
reductase inhibitor.
[0022] (7) An ophthalmic composition for treatment of dry eye
syndrome, which comprises, as an active ingredient, an aldose
reductase inhibitor.
[0023] (8) An ophthalmic composition for treatment of
hypolacrimation, which comprises, as an active ingredient, an
aldose reductase inhibitor.
[0024] (9) The ophthalmic composition described in any of (6) to
(8), wherein the aldose reductase inhibitor is a compound
represented by the general formula (I): 4
[0025] wherein A and B are independently lower alkylene, and X, Y,
and Z are independently halogen, or a pharmacologically acceptable
salt thereof.
[0026] (10) The ophthalmic composition described in (9), wherein A
and B are methylene, X is chlorine, Y is bromine, and Z is
fluorine.
[0027] (11) The ophthalmic composition described in any of (6) to
(10) which are in the form of preparations for eye local
administration.
[0028] (12) A method for treating diabetic corneal lesion and/or
deteriorated corneal esthesia which comprises administering an
effective amount of a compound represented by the general formula
(I): 5
[0029] wherein A and B are independently lower alkylene, and X, Y,
and Z are independently halogen, or a pharmacologically acceptable
salt thereof, to a subject in need of a treatment of diabetic
corneal lesion and/or deteriorated corneal esthesia.
[0030] (13) A method for treating non-diabetic corneal lesion which
comprises administering an effective amount of an aldose reductase
inhibitor to a subject in need of a treatment of non-diabetic
corneal lesion.
[0031] (14) A method for treating dry eye syndrome which comprises
administering an effective amount of an aldose reductase inhibitor
to a subject in need of a treatment of dry eye syndrome.
[0032] (15) A method for treating hypolacrimation which comprises
administering an effective amount of an aldose reductase inhibitor
to a subject in need of a treatment of hypolacrimation.
[0033] (16) Use of a compound represented by the general formula
6
[0034] wherein A and B are independently lower alkylene, and X, Y,
and Z are independently halogen, or a pharmacologically acceptable
salt thereof, in the manufacture of an ophthalmic composition for
the treatment of diabetic corneal lesion and/or deteriorated
corneal esthesia.
[0035] (17) Use of an aldose reductase inhibitor in the manufacture
of an ophthalmic composition for the treatment of non-diabetic
corneal lesion.
[0036] (18) Use of an aldose reductase inhibitor in the manufacture
of an ophthalmic composition for the treatment of dry eye
syndrome.
[0037] (19) Use of an aldose reductase inhibitor in the manufacture
of an ophthalmic composition for the treatment of
hypolacrimation.
BEST MODE FOR CARRYING OUT THE INVENTION
[0038] The terms in the general formula (I) of this specification
are defined as follows:
[0039] A and B are independently lower alkylene. Lower alkylene as
used in this specification mean straight or branched alkylene
groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
In the concrete, they are methylene, ethylene, trimethylene,
propylene groups, and the like, among which methylene and ethylene
groups are desirable.
[0040] X, Y, and Z are independently halogen (chlorine, bromine,
fluorine, iodine), and it is particularly desirable when X is
chlorine, Y is bromine, and Z is fluorine.
[0041] In this invention the compound of the formula (II): 7
[0042] having methylene for each of A and B, chlorine for X,
bromine for Y, and fluorine for Z in the general formula (I), i.e.
[3-(4-bromo-2-fluorobenzyl)-
7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazo- lin-1-yl]acetate, is
particularly suitable.
[0043] The compound and pharmacologically acceptable salts thereof
included in this invention as the active ingredient are publicly
known compounds, which can be produced for example with the method
described in the Japanese Published Unexamined Patent Publication
No. Sho 62-96476 (European Patent Publication No. 0218999, U.S.
Pat. No. 4,734,419) or a method based on this method.
[0044] Pharmacologically acceptable salts of the compound in this
invention include salts with basic compounds such as inorganic
bases (e.g. sodium, potassium, calcium, magnesium, aluminum,
ammonium, etc.), and organic bases (e.g. primary amines such as
ethanolamine; secondary amines such as diethylamine,
diethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine ,
etc.; tertiary amines such as trimethylamine, triethylamine,
pyridine, picoline, triethanolamine, etc.; and so on) and the
like.
[0045] The compound and pharmacologically acceptable salts thereof
are effective in prevention, cure, relief/arrestation/relief of
development of symptoms of diabetic corneal lesions, and in
improvement of deteriorated corneal esthesia in mammals including
man, ox/cow, horse, dog, mouse, and rat etc., being the active
ingredient in the ophthalmic composition comprising preparations
for treatment of diabetic corneal lesion and/or those for treatment
of deteriorated corneal esthesia in mammals.
[0046] This invention also provides ophthalmic compositions of
which active ingredient is an aldose reductase inhibitor. The fact
that compounds that can inhibit aldose reductase are excellent in
treatment of non-diabetic corneal lesions as well as symptoms of
dry eye syndrome, particularly hypolacrimation including decreased
basal tear secretion, is a new finding.
[0047] Aldose reductase inhibitors included in this invention as
the active ingredient are not specified if they can inhibit aldose
reductase, being exemplified in the concrete by the compounds
represented by the general formula (I), particularly the compound
of the formula (II), and also by epalrestat, ponalrestat,
tolrestat, sorbinil, methosorbinil, imirestat,
2,3-dihydro-2,8-bis(1-methylethyl)-3-thioxo-4H-1,4-benzoxazine-
-4-acetic acid (AD5467),
6-fluoro-2,3-dihyro-2',5'-dioxo-(2S-cis)-spiro[4H-
-1-benzopyran-4,4'-imidazolidine]-2-carboxyamide (SNK-860),
8-chloro-2',3'-dihydro spiro[pyrolzine-3,6'(5,
)-pyrolo[1,2,3-de]-[1,4]be- nzoxazine]2,5,5'-trion (ADN138), and
5-(3-ethoxy-4-pentyloxyphenyl)-2,4-th- iazolidinedion (CT-112),
etc. Particularly suitable are the compounds represented by the
general formula (I), especially the compounds shown by the formula
(II).
[0048] Aldose reductase inhibitors are effective in prevention,
cure, relief/arrestation/relief of development of symptoms of
diabetic corneal lesion, and in cure of symptoms of dry eye
syndrome, particularly in improvement of hypolacrimation including
decreased basal tear secretion in mammals including man, ox/cow,
horse, dog, mouse, and rat, etc. They are the active ingredient in
the ophthalmic composition for mammals comprising preparations for
treatment of non-diabetic corneal lesion, for treatment of dry eye
syndrome, and/or for treatment of hypolacrimation.
[0049] As described above, diabetic corneal lesion in this
invention means various corneal lesions derived from diabetes,
including, in the concrete, diabetic punctate superficial
keratoepitheliosis, diabetic recurrent erosion of keratoepithelium,
and diabetic delayed defect of keratoepithelium. Non-diabetic
corneal lesions are, as described above, those caused by
non-diabetic pathological, such as inflammation, allergy,
microorganisms, chemicals, caustic effect of acids or alkalis,
dryness, foreign bodies, burn, etc. Deteriorated corneal esthesia
in this invention means the pathological conditions where the
corneal esthesia has been deteriorated as the result of aging,
diseases such as corneal herpes and diabetes, etc., use of contact
lens, and ophthalmologic surgery (surgery for cataract, corneal
transplantation, surgery for retinal detachment, etc.). Diseases
accompanied with dry eye syndrome include, as described above,
hypolacrimation, alacrima, xerophthalmia, Sjogren's syndrome, dry
keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid,
marginal blepharitis diabetes, etc. and dry eye syndrome is also
noted after surgery for cataract, or accompanied with allergic
conjunctivitis, etc. Dry eye syndrome is observed in
hypolacrimation due to increased VDT tasks or dry air in
air-conditioned rooms. Hypolacrimation means abnormal (decreased or
stopped) tear secretion due to some causes, including abnormal
basal tear secretion.
[0050] Treatment with the ophthalmic composition includes all
controls, including prevention, cure, relief/arrestation/relief of
development, etc. The treatment of corneal lesion is also effective
in intractable corneal lesion in advanced conditions, i.e. with
advanced erosion or detachment.
[0051] Ophthalmic compositions of this invention may be
administered orally or parenterally, but use in the form of
preparations for eye local administration is particularly desirable
when the avoidance of the influence on other areas of the
cardiovascular system and the significance of their actual
effectiveness, etc. are taken into account.
[0052] Such dosage forms include eye drops, eye ointments, powders,
granules, tablets, capsules, injections, etc., among which eye
drops and eye ointments are particularly suitable. Preparations in
such dosage forms can be produced with the conventional means.
[0053] Aqueous solutions and diluents for suspensions used in
preparation of eye drops are distilled water, physiological saline,
and the like, and non-aqueous solutions and diluents for
suspensions include vegetable oil, liquid paraffin, mineral oil,
propylene glycol, p-octyldodecanol, etc.
[0054] In addition, various additives may be contained in eye drops
as needed, including buffering agents, isotonizers, preservatives,
thickeners, stabilizers, antioxidants, pH-adjusting agents,
chelating agents, etc. Buffering agents are added to keep the pH
constant, for example at 5.0 to 8.0, including borate buffer,
citrate buffer, tartrate buffer, phosphate buffer, acetate buffer,
etc. Such a buffer is added in an amount that is suitable for the
purpose of buffering, i.e. that can keep the pH value constant in
the range as described above.
[0055] Isotonizers are added to make the preparation isotonic with
the tear, including sugars such as glucose, mannitol, sorbitol,
etc.; polyhydric alcohols such as glycerol, polyethylene glycol,
propylene glycol, etc.; and salts such as sodium chloride, sodium
citrate, etc. Such an isotonizer is added in an amount that makes
the osmotic pressure of the eye drop equal to that of the tear.
Preservatives used are benzalkonium chloride, parabens,
chlorobutanol, etc. As pointed out above, some preservatives such
as benzalkonium chloride, chlorobutanol, etc. have been reported to
impair the cornea, but these preservatives may be added because the
preparations of this invention are capable of improving the corneal
lesion.
[0056] Thickeners that can be used include glycerol, carboxymethyl
cellulose, carboxyvinyl polymers, etc.; stabilizers such as sodium
sulfite, propylene glycol, etc.; antioxidants such as ascorbic
acid, sodium ascorbate, tocopherol, sodium thiosulfate, etc.;
pH-adjusting agents such as hydrochloric acid, citric acid,
phosphoric acid, acetic acid, tartaric acid, sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.:
and chelating agents such as sodium edetate, sodium citrate,
etc.
[0057] Eye drops are prepared by aseptic manipulation, or
sterilization is performed at a suitable stage of preparation.
[0058] Eye ointments can be aseptically prepared by mixing the
active ingredient into the base usually used for preparation of eye
ointments followed by formulation into pharmaceutical preparations
with a conventional method. Bases for eye ointments are exemplified
by vaseline, jelene 50, plastibase, macrogol, etc., and surfactants
may be added to increase hydrophilia. Additives described above,
for example preservatives, may be contained in eye ointments as
needed.
[0059] In addition, ingredients having pharmacological activity
different from that of the ingredient of this invention may be
added as needed to the pharmaceutical preparations of this
invention if they are compatible to the purpose of the
invention.
[0060] The dose and dosing frequency of the active ingredient of
this invention vary according to the symptoms of the disease to be
treated, age and body weight of the patient, dosage form, treatment
duration, therapeutic effect desired, etc. In general, for local
ophthalmic administration, it brings about a satisfactory effect
for an adult, that in case of use as an eye drop, of the
preparation containing 0.001 to 10.0 w/v %, preferably 0.01 to 1.0
w/v %, of the compound of this invention or a pharmacologically
acceptable salt thereof or an aldose reductase inhibitor may be
administered several times, preferably 1 to 6 times in an eye, a
day and several drops, preferably 1 to 4 drops at a time, and in
case of use as an eye ointment, of the preparation containing 0.001
to 10.0 w/v %, preferably 0.01 to 1.0 w/v %, of the compound of
this invention or a pharmacologically acceptable salt thereof or an
aldose reductase inhibitor may be applied several times, preferably
1 to 6 times in an eye, a day.
[0061] In this invention, one active ingredient alone or two or
more active ingredients in combination may be contained in the
preparation. In the preparation that contains two or more active
ingredients, the amount of each ingredient may be determined
appropriately according to the therapeutic effect and safety of
each ingredient.
EXAMPLES
[0062] This invention is explained in the concrete in the Examples
described below, and the invention is not limited at all by these
Examples.
Experimental Example 1
Influence on the Repair Process of the Wound of Keratoepithelial
Detachment in Alloxan-induced Diabetic Rabbits
[0063] 1) Test Animals and Procedures to Induce Diabetes
[0064] Alloxan monohydrate (Lot No. DLJ5619, M.W. 160.09 Wako Pure
Chemical Industries, LTD.) of 80 mg/kg was dissolved in 2 mL of
physiological saline, and the solution was administered once
intravenously of male Japanese albino rabbits [Std: JW/CSK]
(11-week-old) to induce diabetes.
[0065] Blood glucose was determined weekly after administration of
alloxan monohydrate: the mean blood glucose was increased from
142.2.+-.4.7 mg/dL (mean.+-.S.E.; The same is applicable
hereinafter.) before administration to 522.5.+-.13.7 mg/dL at 1
week, and this elevated level persisted thereafter. Animals with
this alloxan-induced diabetes were used in the experiment.
[0066] 2) Detachment of Keratoepithelium
[0067] Under nembutal anesthesia a circular filter paper of TOYO
No. 2 7.0 mm in diameter permeated with 7 .mu.L of n-heptanol was
kept in contact with the surface at the central part of the cornea
for 1 minute, and the keratoepithelium was detached by removal of
the filter paper from the cornea. Then the surface of the wound due
to detachment was washed thoroughly with physiological saline.
[0068] 3) Measurement of the Area of the Wound of Keratoepithelial
Detachment
[0069] The cornea was stained with fluorescein, and photographs of
the anterior ocular segment were taken with the Medical Nikkor Lens
attached with a yellow filter (Kodak WRATTEN No.12) and the front
part of the flash attached with a blue filter (Kodak WRATTEN
No.47). On the projected photographs magnified to the same degree,
the stained area was measured with the planimeter. This area was
taken as the area of the wound of keratoepithelial detachment
(un-repaired region).
[0070] The test substance was instilled every 4 hours after the
keratoepithelial detachment (the first instillation was made
immediately after preparation of the wound of keratoepithelial
detachment).
[0071] Twelve hours after the keratoepithelial detachment, the area
of the wound was measured. Then its relative value was calculated
by taking the area of the wound immediately after the
keratoepithelial detachment as 100. This relative value was used to
assess the extent of repair.
[0072] 4) Method of Administration
[0073] The compound of the formula (II), i.e.
[3-(4-bromo-2-fluorobenzyl)--
7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]acetate, an
active ingredient of this invention, was used for preparation of a
0.1% eye drop, and the eye drops were used as the test substance.
The vehicle control was the vehicle of the eye drop after exclusion
only of the active ingredient.
[0074] Every 4 hours from immediately after the keratoepithelial
detachment, the test substance was instilled at the volume of 30
.mu.L/eye into the unilateral eye of a rabbit by using a Pipetman,
while the vehicle control was instilled at 30 .mu.L/eye into the
contralateral eye.
[0075] 5) Statistical Analysis
[0076] The area of the un-repaired wound in the test
substance-instilled eye was compared with that in the vehicle
control substance-instilled eye with the Student's t-test. The
results are shown in Table 1.
1 TABLE 1 Relative area of wound of keratoepithelial detachment 12
hours after keratoepithelial detachment (%) n Test group 89.0 .+-.
2.7* 5 Control 96.5 .+-. 2.0 10 *: p < 0.05
[0077] The difference was judged to be significant because the
level of significance was below 5%.
Experimental Example 2
Influence on the Repair Process of the Wound of Keratoepithelial
Detachment in Normal Rabbits
[0078] In the Experimental Example 1, the influence in rabbits with
alloxan-induced diabetes was investigated, while the influence in
normal (not diabetic) rabbits was investigated in this Example.
[0079] 1) Test Animals
[0080] Ten-week-old male New Zealand White rabbits (weighing
2.07.+-.0.11 kg: mean weight at the start of the experiment) were
acclimation period for 7 days, while the animals were examined for
the general signs including diarrhea and body weight, etc., and the
anterior ocular segment was also observed. Only animals without any
abnormality were used in the experiment.
[0081] 2) Detachment of Keratoepithelium
[0082] Keratoepithelial detachment wounds were prepared as
described in the Experimental Example 1.
[0083] 3) Measurement of Area of the Keratoepithelial Detachment
Wound
[0084] The test substance was instilled every 4 hours after the
keratoepithelial detachment (the first instillation was made
immediately after preparation of the wound of keratoepithelial
detachment).
[0085] Twelve hours after the keratoepithelial detachment, the area
of the wound was measured, and its relative value was calculated by
taking the area of the wound immediately after the keratoepithelial
detachment as 100, and the relative value was used to assess the
extent of repair. The area of the wound of keratoepithelial
detachment was measured as described in the Experimental Example
1.
[0086] 4) Method of Administration
[0087]
[3-(4-Bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-1-yl]acetate, an active ingredient of this invention,
having aldose reductase-inhibiting effect was used for preparation
of 0.2% eye drops, and the eye drops were used as the test
substance. The vehicle control was the vehicle of the eye drops
simply without the active ingredient.
[0088] Every 4 hours from immediately after the keratoepithelial
detachment, the test substance was instilled at the volume of 30
.mu.L/eye into the unilateral eye of a rabbit by using a Pipetman,
while the control substance was instilled at 30 .mu.L/eye into the
contralateral eye.
[0089] 5) Statistical Analysis
[0090] The area of un-repaired wound in the test substance-treated
eye was compared with that in the vehicle control treated eye with
the Student's t-test. The results are shown in Table 2.
2 TABLE 2 Relative area of wound of keratoepithelial detachment 12
hours after keratoepithelial detachment (%) n test group 80.8 .+-.
2.O** 6 control 88.8 .+-. 1.0 6 group **: p < 0.01
[0091] The difference was judged to be significant because the
level of significance was below 1%.
Experimental Example 3
Influence on the Deteriorated Corneal esthesia and Hypolacrimation
in Alloxan-induced Diabetic Rabbit
[0092] 1) Test Animals and Procedure to Induced Diabetes
[0093] Alloxan monohydrate (Lot No. DLJ5619, M.W. 160.09 Wako Pure
Chemical Industries, LTD.) of 80 mg/kg was dissolved in 2 mL of
physiological saline, and the solution was administered once
intravenously of male Japanese albino rabbits [Std: JW/CSK]
(11-week-old) to induce diabetes.
[0094] Blood glucose was determined once a week on 4 times after
administration of alloxan monohydrate: animals having always blood
glucose of 300 mg/dL or more were used as diabetic animals in this
Experiment.
[0095] 2) Method of Administration
[0096]
[3-(4-Bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-1-yl]acetate, an active ingredient of this invention,
having aldose reductase-inhibiting effect was used for preparation
of a 0.3% eye drops, and the eye drops were used as the test
substance. The vehicle control was the vehicle of the eye drops
simply without the active ingredient.
[0097] At the time of intravenous administration of alloxan, the
drug was instilled into both eyes at 30 .mu.L/eye four times a day
over 4 consecutive weeks. Sixteen eyes of 8 animals in each of the
test substance group and the vehicle control group were subjected
to the examination of corneal esthesia and the examination of tear
secretion as follows.
[0098] 3) Examination of Corneal Esthesia
[0099] One hour after the second instillation on the day of
examination, each animal was fixed in a stainless steel fixator
(SHIBATA GLASS WORKS). The central part, the most sensitive part,
of the cornea was stimulated 10 times in rapid sequence with a
pressure by applying at the right angle a 30 mm nylon thread (Toray
Nylon Monofilament, Type 100, No.0.6, diameter .phi.: 0.027 mm,
cross section s: 0.0129) of the Cochet-Bonnet type esthesiometer
(Handaya Co., Ltd.) so that the nylon thread might be bent only
slightly (pressure: 5.19 g/mm.sup.3, measured by Handaya), and the
number of blink reflex was taken as the corneal esthesia value. The
examination was performed before, 2 weeks after and 4 weeks after
administration of alloxan.
[0100] 4) Examination of Tear Secretion (Schirmer's Test)
[0101] One hour after the second instillation on the day of
examination, each animal was fixed in a stainless steel fixator,
and the edge of the Schirmer's test paper (SHOWA YAKUHIN KAKO, Co.,
Ltd., Lot No.70080) was inserted into the conjunctival sac to cover
the 1/3 of the lower eyelid on the ear side. One minute after, the
paper was removed, and the length of the moistened part was read
from the scale on the paper. The examination was performed before
and 4 weeks after administration of alloxan in each group.
[0102] 5) Statistical Analysis
[0103] In both examinations, the test substance group and the
vehicle control group were compared with the Williams's test.
[0104] The results of the examination of corneal esthesia are shown
in Table 3, and those of the examination of tear secretion in Table
4.
3 TABLE 3 Coreneal esthesia value (number of times) Before After 2
After 4 alloxan weeks weeks n test group 5.6 .+-. 0.3 5.3 .+-.
0.7** 5.1 .+-. 0.6** 16 control 5.3 .+-. 0.5 3.5 .+-. 0.5 2.6 .+-.
0.4 16 group **: p < 0.01
[0105]
4 TABLE 4 tear secretion (mm: Schirmer`s test) before alloxan After
4 weeks n test group 8.3 .+-. 0.6 7.1 .+-. 0.4** 16 control group
8.2 .+-. 0.4 4.8 .+-. 0.4 16 **: p < 0.01
[0106] In both Tables, difference was judged to be significant
because the level of significance was below 1%.
Experimental Example 4
Influence on decreased Basal Tear Secretion and Keratoepithelial
Lesion in Rabbits with Dry Eye Syndrome Induced by Trigeminal
Denervation
[0107] 1) Test Animals
[0108] Twenty male Japanese albino rabbits [Std:JW/CSK] were
used.
[0109] 2) Trigeminal Denervation
[0110] a) Operational Procedure
[0111] Urethane (ALDRICH, Lot No.069110Q) was intraperitoneally
administered at the dose of 1 g/kg to rabbits of which hair at the
head after anesthesia had been shaved.
[0112] After disinfection of the shaved area, midline incision of
the skin was made from the frontal bone to the ear root, and the
periosteum and the muscular tissue around the temporal bone and
mandibular 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 using a 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 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 cranial
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 of the trigeminal nerve (ocular
nerve) and the second branch (maxillary nerve), were pulled
laterally and cut with corneoscleral scissors.
[0113] After confirmation of miosis of the ipsilateral eye
immediately after the cut, 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 intramuscularly at the dose of 0.1 mL/kg.
[0114] The trigeminal denervation was made only on the left eye
side, while the trigeminal denervation on the right eye side or
sham operation was not made.
[0115] b) Acclimation Period
[0116] Two-week acclimation period was allowed to pass after the
trigeminal denervation.
[0117] Only animals that showed decreased basal tear secretion and
keratoepithelial lesion in this period were used in the
experiment.
[0118] 3) Method of Administration
[0119]
[3-(4-Bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroqu-
inazolin-1-yl]acetate, an active ingredient of this invention,
having aldose reductase-inhibiting effect was used for preparation
of 0.03% eye drop, 0.1% eye drop, and 0.3% eye drop, which were
used as the test substances. The vehicle control was the base of
the eye drops simply without the active ingredient.
[0120] From about 2 weeks after the trigeminal denervation, one of
the above-mentioned drugs was instilled at the volume of 30
.mu.L/eye four times a day for 2 consecutive weeks. Five eyes of
each of the test substance groups and the control group were
examined for the basal tear secretion and the keratoepithelial
lesion as follows.
[0121] 4) Examination
[0122] a) Basal Tear Secretion
[0123] Before the start of instillation (Week 0), and 1 week and 2
weeks after instillation, the basal tear secretion was measured one
hour after the second instillation on the day of examination.
[0124] Keratoconjunctiva was anesthetized by instillation of 4%
lidocaine (Xylocaine.RTM. 4% for ophthalmology: Fujisawa
Pharmaceutical Co., Ltd.), and the eye drop and the tear around the
eyelid were wiped off about 5 minutes later.
[0125] When loss of keratoconjunctival esthesia was confirmed with
the Cochet-Bonnet type esthesiometer, the edge of the Shirmer's
test paper was kept inserted into the conjunctival sac for 5
minutes, and the length of the moistened part was read from the
scale on the paper.
[0126] The basal tear secretion was expressed by the mean per
minute calculated from the 4-minute-value obtained by subtraction
of the first-1-minute-value from the 5-minute-value of the
Shirmer's test, so that the volume of the tear considered to be
retained in the conjunctival sac might be excluded.
[0127] b) Keratoepitherial Lesion
[0128] Before the start of instillation (Week 0), and 1 week and 2
weeks after instillation, the lesion was evaluated one hour after
the first instillation on the day of examination.
[0129] 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, followed by vital staining of the
keratoconjunctival epithelium for evaluation of the extent of
lesion according to the scoring system shown in Table 5.
5TABLE 5 Score Stained area of keratoconjunctiva 0 None 0.5 A part
stained slightly 1 Less than 1/4 2 More than 1/4 and less than 1/2
3 More than 1/2 and less than 3/4 4 More than 3/4
[0130] 5) Results
[0131] The results of the examination of basal tear secretion and
those of the examination of keratoepithelial lesion are shown in
Table 6 and in Table 7, respectively. The results of statistical
analyses are also shown in the Tables.
6 TABLE 6 Basal tear Number secretion of eyes Time point (week)
(mm/minute) Before 20 -- 1.28 .+-. 0.16 operation Acclimation 20 1
0.39 .+-. 0.05[**] period 20 2 0.38 .+-. 0.06[**] Control group 5
Before instillation 0.40 .+-. 0.15* 5 1 0.58 .+-. 0.21[*] 5 2 0.54
.+-. 0.12[**] Test group 5 Before instillation 0.38 .+-. 0.09[**]
0.03% 5 1 0.92 .+-. 0.17# 5 2 1.02 .+-. 0.09##+ Test group 5 Before
instillation 0.38 .+-. 0.13[**] 0.1% 5 1 1.24 .+-. 0.14##+ 5 2 1.12
.+-. 0.11##++ Test group 5 Before instillation 0.34 .+-. 0.10[**]
0.3% 5 1 1.24 .+-. 0.16##+ 0.3% 5 2 1.20 .+-. 0.15##++ #p<0.05
##p<0.01: comparison with the value before instillation in each
group (Student`s t-test) *p<0.05 **p<0.01: comparison with
the value before operation (Student`s t-test) [*]p<0.05
[**]p<0.01: comparison with the value before operation
(Aspin-Welch test) +p<0.05 ++p<0.01: comparison with the
value at the corresponding time point in the control group
(Dunnett`s test)
[0132]
7 TABLE 7 Number Keratoepithelial of eyes Time point (week) lesion
(score) Before 20 -- 0.0 .+-. 0.0 operation Acclimation 20 1 2.4
.+-. 0.2[**] period 20 2 2.9 .+-. 0.2[**] Control group 5 Before
instillation 2.8 .+-. 0.6[**] 5 1 1.4 .+-. 0.4[*] 5 2 1.1 .+-.
0.2#[*] Test group 5 Before instillation 2.8 .+-. 0.4[**] 0.03% 5 1
0.5 .+-. 0.4[##] 5 2 0.2 .+-. 0.1[##]++ Test group 5 Before
instillation 3.0 .+-. 0.6[**] 0.1% 5 1 0.4 .+-. 0.2## 5 2 0.4 .+-.
0.2[##]+ Test group 5 Before instillation 3.0 .+-. 0.5[**] 0.3% 5 1
0.5 .+-. 0.4## 5 2 0.1 .+-. 0.1##++ #p<0.05 ##p<0.01:
comparison with the value before instillation in each group
(Student`s t-test) [#]p<0.05 [##]p<0.01: comparison with the
value before instillation (Aspin-Welch test) [*]p<0.05
[**]p<0.01: comparison with the value before operation
(Aspin-Weich test) +p<0.05 ++p<0.01: comparison with the
value at the corresponding time point in the control group
(Dunnett`s test)
INDUSTRIAL APPLICABILITY
[0133] The ophthalmic compositions of this invention comprising the
compound of this invention or a pharmacologically acceptable salt
thereof as the active ingredient are effective in prevention, cure,
relief of the symptoms, etc. of diabetic corneal lesions,
particularly severe diabetic corneal lesion (e.g. in repair of the
wound of keratoepithelial detachment), and also in improvement of
the deteriorated corneal esthesia. Therefore the ophthalmic
compositions of this invention are suggested to be useful for
treatment of diabetic corneal lesion and for treatment of
deteriorated corneal esthesia.
[0134] The ophthalmic compositions of this invention containing the
compound or a pharmacologically acceptable salt thereof or an
aldose reductase inhibitor as the active ingredient are effective
also in prevention, cure, relief of the symptoms, etc. of
non-diabetic corneal lesions (e.g. in repair of the wound of
keratoepithelial detachment) and in cure of symptoms of dry eye
syndrome (e.g. in improvement of hypolacrimation including
decreased basal tear secretion). Therefore they are suggested to be
useful for treatment of non-diabetic corneal lesion, treatment of
dry eye syndrome, and for treatment of hypolacrimation.
* * * * *