CA1330946C - Topical preparation for treating otopathy containing ofloxacin or a salt thereof - Google Patents
Topical preparation for treating otopathy containing ofloxacin or a salt thereofInfo
- Publication number
- CA1330946C CA1330946C CA000595126A CA595126A CA1330946C CA 1330946 C CA1330946 C CA 1330946C CA 000595126 A CA000595126 A CA 000595126A CA 595126 A CA595126 A CA 595126A CA 1330946 C CA1330946 C CA 1330946C
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- Prior art keywords
- ofloxacin
- salt
- otopathy
- treating
- topical preparation
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Orthopedics, Nursing, And Contraception (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A topical preparation for treating otophathy which contains ofloxacin or a salt thereof as an active ingerdient is disclosed.
A topical preparation for treating otophathy which contains ofloxacin or a salt thereof as an active ingerdient is disclosed.
Description
:
~. 3 ~
'rOPICAL PREPARATION FOR TREAT ING OTOPATHY ~ ~
FIELD OF THE INVENTION :: ::
This invention relates to a topical preparation ~ .:
. ~ ,.
for treating otopathy which contains ofloxacin or a salt thereof as an active lngredient.
BACKGROUND OF THE INVENTION
: Conventionally employed topical preparation for ;;~
~- treating otopathy include solutions -containing ;~
antibioticsf. such...as . fradiomycin,.. kanamyc.in, chloramphenicol, and cefmenoxime.
Howeverl it has been pointed out that these preparations have oto:toxicity as side effects or . .
:~ therapeutic effects thereof tend to be decreased due to 15 emergence of resistant microorganisms. -. .-.~.. i.
~ SUMMARY:OF THE INVENTION .. `.
; In order to overcome the above-described problems, .
: the inventors have conducted extensive investigations and, ,, : as a result, reached the present invention. .. :.`;
~ The present invention relates to a topical preparation for treating otopathy which contains ofloxacin or a salt thereof as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION .. ; .............. .:
The salt of ofloxacin includes acid addition salt~
25 formed with organic or inorganic acids, e.g., hydrochloric .
1 acid, and salts formed fro~ the carboxyl group and an alkali metal, e.g., sodium and potassium.
The otopathy on which the preparation of the present invention is effective includes inflammatory otopathy, such as otitis media and otitis externa, and ~ particularly purulent otitis meclia, circumscript external : otitis and diffuse external otitis.
Dose forms of the topical preparation of the present invention -include spraysï -otic-solutions-, e.g.., ; l.Q intratympanic.in3ections.and ear drops.,..~intmen.ts~...and.the like.
The solutions can be prepared by dissolving ofloxacin in water, physiological saline, or an ~ appropriate buffer, adding, if desired, antiseptics, e.g., :~ 15 methyl p-hydroxybenzoate and benzalkonium chloride, to the ofloxacin aqueous solution, and adjusting the solution to : a p~ in a neutral region. The concentration of ofloxacin . . :
in the aqueous solution usually ranges from about 0.05 to ~: about 2% w/v, and preferably from 0.1 to 1% wjv. The ointments can be~prepared~in a usual manner.
`: In administration- of the ofloxac~n solution, -:~
several 0.5 m~-doses per day are `applied to the external ,; , , ~ ~ , auditory canal by spreading, spraying or instillation, or intratympanically injected through a puncture of the :
~ 3 3 ~
1tympanic membrane. The ofloxacin ointment can be applied to the external auditory canal in an adequate dose. ~
Ofloxacin is of high safety. Acute toxicity ~ :
(LD50) of ofloxacin was found to be 5450 mg/kg ~p.o.) in :
5mice, 200 mg/kg or more (p.o.) in dogs, and from 500 to 1,000 mg/kg (p.o.) in monkeys.
The preparation according to the present invention exhibits marked improvements over the conventional drugs - in terms- of- not - only~-ototoxicity--but also t-issue - ., :.
~ O-- distribution and..... excellent.. .ther.apeu.ti.c.. ef.fec.ts.. on ........... -. :
- otopathy, particularly otitis- media and otit~s externa.
Accordingly, the preparation of the present invention is useful as a topical preparation for treating otopathy. ..
The present invention is now illustrated in .. .~.
15greater detail with reference to the following Examples ..... ~
and Test Examples, but the present invention is not deemed ;;~ :.
., to be limited thereto.
Ofloxacin was dissolved in distilled water for :~: 20injection, and the solution was adjusted to a pH of from ~ ` 6.0 to 7.0, followed by bactericidal filtration to prepare . -~
; ~ -~ a 0.5~ ofloxacin aqueous solution. : ~:~
, :~ 25 .
, ~ .
~. 3 ~
'rOPICAL PREPARATION FOR TREAT ING OTOPATHY ~ ~
FIELD OF THE INVENTION :: ::
This invention relates to a topical preparation ~ .:
. ~ ,.
for treating otopathy which contains ofloxacin or a salt thereof as an active lngredient.
BACKGROUND OF THE INVENTION
: Conventionally employed topical preparation for ;;~
~- treating otopathy include solutions -containing ;~
antibioticsf. such...as . fradiomycin,.. kanamyc.in, chloramphenicol, and cefmenoxime.
Howeverl it has been pointed out that these preparations have oto:toxicity as side effects or . .
:~ therapeutic effects thereof tend to be decreased due to 15 emergence of resistant microorganisms. -. .-.~.. i.
~ SUMMARY:OF THE INVENTION .. `.
; In order to overcome the above-described problems, .
: the inventors have conducted extensive investigations and, ,, : as a result, reached the present invention. .. :.`;
~ The present invention relates to a topical preparation for treating otopathy which contains ofloxacin or a salt thereof as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION .. ; .............. .:
The salt of ofloxacin includes acid addition salt~
25 formed with organic or inorganic acids, e.g., hydrochloric .
1 acid, and salts formed fro~ the carboxyl group and an alkali metal, e.g., sodium and potassium.
The otopathy on which the preparation of the present invention is effective includes inflammatory otopathy, such as otitis media and otitis externa, and ~ particularly purulent otitis meclia, circumscript external : otitis and diffuse external otitis.
Dose forms of the topical preparation of the present invention -include spraysï -otic-solutions-, e.g.., ; l.Q intratympanic.in3ections.and ear drops.,..~intmen.ts~...and.the like.
The solutions can be prepared by dissolving ofloxacin in water, physiological saline, or an ~ appropriate buffer, adding, if desired, antiseptics, e.g., :~ 15 methyl p-hydroxybenzoate and benzalkonium chloride, to the ofloxacin aqueous solution, and adjusting the solution to : a p~ in a neutral region. The concentration of ofloxacin . . :
in the aqueous solution usually ranges from about 0.05 to ~: about 2% w/v, and preferably from 0.1 to 1% wjv. The ointments can be~prepared~in a usual manner.
`: In administration- of the ofloxac~n solution, -:~
several 0.5 m~-doses per day are `applied to the external ,; , , ~ ~ , auditory canal by spreading, spraying or instillation, or intratympanically injected through a puncture of the :
~ 3 3 ~
1tympanic membrane. The ofloxacin ointment can be applied to the external auditory canal in an adequate dose. ~
Ofloxacin is of high safety. Acute toxicity ~ :
(LD50) of ofloxacin was found to be 5450 mg/kg ~p.o.) in :
5mice, 200 mg/kg or more (p.o.) in dogs, and from 500 to 1,000 mg/kg (p.o.) in monkeys.
The preparation according to the present invention exhibits marked improvements over the conventional drugs - in terms- of- not - only~-ototoxicity--but also t-issue - ., :.
~ O-- distribution and..... excellent.. .ther.apeu.ti.c.. ef.fec.ts.. on ........... -. :
- otopathy, particularly otitis- media and otit~s externa.
Accordingly, the preparation of the present invention is useful as a topical preparation for treating otopathy. ..
The present invention is now illustrated in .. .~.
15greater detail with reference to the following Examples ..... ~
and Test Examples, but the present invention is not deemed ;;~ :.
., to be limited thereto.
Ofloxacin was dissolved in distilled water for :~: 20injection, and the solution was adjusted to a pH of from ~ ` 6.0 to 7.0, followed by bactericidal filtration to prepare . -~
; ~ -~ a 0.5~ ofloxacin aqueous solution. : ~:~
, :~ 25 .
, ~ .
- 3 ~
: :.
~ .
.~; ~ :' .' ~`~
3 ~
:
Ofloxacin was dissolved in physiological saline, and the solution was treated in the same manner as in Example 1 to prepare an ofloxacin solution. :
Ofloxacin was dissolved in physiological saline, and the solution was treated in the same manner as in ~;~ Example 1 to prepare a 0.3% ofloxacin aqueous solution.
TEST EXAMPLE-l~
, . : .
I0 1) Test Method~
~~ Fifteen white guinea~pigs were divided into the following two groups: 10 in an ofloxacin group topically administered with a 0.3% ofloxacin solution (hereinafter referred to as ~l0.3% OFLX group") and 5 in a control group ~15 ~ administered with physiological saline.
Before testing, the auditory brain-stem response (herelnafter referred to as "ABR") of each animal was determined to obtain a response threshold. A ~ogon sound wave having a frequency of 10,000 was used as a stimulating sound.
The left tympanic;membrane was punctured under general anesthesia, and 0.2 me of the ofloxacin solution of Example~ 3 or 0.2 m~ of the control solution (physlological saline) was injected~ into the tympanic :, ~ .
~.
: :.
~ .
.~; ~ :' .' ~`~
3 ~
:
Ofloxacin was dissolved in physiological saline, and the solution was treated in the same manner as in Example 1 to prepare an ofloxacin solution. :
Ofloxacin was dissolved in physiological saline, and the solution was treated in the same manner as in ~;~ Example 1 to prepare a 0.3% ofloxacin aqueous solution.
TEST EXAMPLE-l~
, . : .
I0 1) Test Method~
~~ Fifteen white guinea~pigs were divided into the following two groups: 10 in an ofloxacin group topically administered with a 0.3% ofloxacin solution (hereinafter referred to as ~l0.3% OFLX group") and 5 in a control group ~15 ~ administered with physiological saline.
Before testing, the auditory brain-stem response (herelnafter referred to as "ABR") of each animal was determined to obtain a response threshold. A ~ogon sound wave having a frequency of 10,000 was used as a stimulating sound.
The left tympanic;membrane was punctured under general anesthesia, and 0.2 me of the ofloxacin solution of Example~ 3 or 0.2 m~ of the control solution (physlological saline) was injected~ into the tympanic :, ~ .
~.
- .. ~.
'.','.";..`.' ~
~...,.:.., ~=~
r~
~ 3 3 ~
1 cavity once a day for consecutive 7 days. ABR was measured after 10 days from the final day of injeation.
2) Result~
The change between the ABR threshold before the administration and that after the administration was shown in Table 1 below.
TABLE 1 . ~
Chanqe of ABR Threshold Threshold (d~, Mean +S.~
Before Admin. After Admin.
0.3% OFLX Group 30 i-1.-3 34.5 i 1.4 Control Group 30 i 1.6 35 ~ 1.6 As is apparent from Table 1, the threshold changes : ~ .
in both of the 0.3% OFLX group and the control group were ~ `~
15slight (4.5 dB and 5.0 dB, respectively), indicating that ~-;~ the reduct1on of acoustic acuity due to the administration -~
of ofloxacin was negligible.
TEST EXAMPLE 2 ~ ;~
1) Test Animal and Administration Route~
20~ Twenty-nine guinea pLgs showing normal Preyer's `~-reflex~Ibody weight: ;250 t~ 350 9) were divided into the following three groups; 12 in a group receiving topical `
administration of 0.5% ofloxacin solution (hereinafter -~
;re~erred to as ll~o.s% OF~X group"); 13 in a group topically 25administered with gentamicin ~hereinafter referred to as :
~ _ 5 _ ~ ~
': . `' , '''.~ "'-` .'."' ~ ~ ~3 ~
1 "GM group"); and 4 in a control group administered with physiological saline.
After ketalar and a muscle relaxant (xylazine) were intramuscularly administere~1, an incision of 2 mm in diameter was made at the middle ear from the posterior portion of the ear of the guinea pig, and a tube of the same diameter was inserted into the tympanic cavity through the opening and sealed and fixed with an adhesive.
- The incision wound was temporarily sutured and closed.-Immediately after the operation, ABR ~as r-ecorded. -From the same day, 0.2 me of a 4% gentamicin solution, 0.2 mC
., ~.,~
of the ofloxacin solution of Example 2, or 0.2 me of the control solution (physiological saline) was injected through the tube into the tympanic cavity. The injection was made once a day for consecutive 10 days. On the 10th day, ABR was again recorded, and the animals were killed. ~ ;
2) ~ethod of Observation:
i) Measurement of ABR: -An ear drum lead was used for the measurement of ABR. The ground electrode was placed on the foreleg of the same side as the injected ear of the guimia pigs. A
clicking sound waB given to the external auditory canal from a tube via a crystal receiver. The auditory response was given as a reaction wave, and an average of 200 measurements obtained by a computer was recorded by an XY
:~ ' '~
- 6 - ~;
3 ~ 5 .
1 recorder. The ABR threshold in the individual animal was obtained from the resulting elec~rocochleogram. ; ;~
ii) Morphological Observation a. Microscopic Observation~
A sample tissue tmiddle ear mucosa) was fixed in - ;
formalin using the auditory bulla in a conventional method. After decalcification, the sample was embedded in paraffine and sliced. The paraffin section was stained ~- with hematoxylin and eosin and microscopi-cally-observed.
:-- - 10 b. Scanning Electronmicroscopic ~EM)~ Observation~
- A sample tissue-(cochlea) was ~horoughly washed in ~;~ a jet stream of physiological 5aline and fixed in a 2.5%
glutaraldehyde solution for 12 hours using a conventional method. Then, the tissue was again washed with a phosphate buffer solution (p~ 7.4) by shaking, fixed in a 1~ osmic acid solution for 1 hour, and electrically .
~ stained with osmium tannate. The tissue was dehyrated ~ .:
with an alcohol using a conventional method and dried at a ~ critical Point, followed by sputtering with platinum ions.
`~ ~ 20 The sample thus prepared was observed under a Hitachi S-570 Model scanning electronmicroscope.
iii) Determination of Distributlon of Ofloxacin Distribution of the drug to the serum, brain tissue, middle ear ;mucosa, and cochlear perilymph was~ ; -~; 25 examined in the control group and the 0.5~ OFLX group. A ~ ~
..: :
... .: .
_ 7 _ ~ - -'~', :,''' , , ,'"'- .'~. '~' ~' ' ~ ~ ~,3~ 'f 1 blood sample was collected ~rom the carotid arteryl and the brain tissue was excised immediately after decapitation. The middle ear mucosa was stripped off after thorough washing of the middle ear cavity with physiological saline. Thereafter, the cochlear perilymph was collected by a glass capillary.
The concentration of the drug in the tissue was biologically assayed according to a paper disc method using B. subtilis ATCC 6051 and E. coli Kp as test micro-organisms.
The serum was used as untreated for the test. The brain tissue was homogenized together with an equal weight of a 0.1M phosphate buffer solution (p~ 7.0) in a glass-, .
made homogenizer to prepare a 50% homogenate solution. ;
Sampling of the perilymph and the middle ear mucosa was carried out within the same time zone, and the ~
samples were pooled in the cold. After measuring the ;
- .
volume of the perilymph the sample was ten-fold diluted ` with a phosphate buffer and tested. On the other hand, ~ .. ..
after weighing and homogenizing, the mucosa sample was tested.
3) Result: -, ~ . , , ., ~ ,. ..
i) Change of Acoustic Acuity: ` `
The change of ABR thresholds are shown in Table 2 below. ~ .~
'. `, ...
,,.:,. ~,,, '`"`.'.'.',".
~:, ::,,.
. ~, ~ 3 ~
., ~ -, ABR Threshold Chanqe Threshold Change ~dB, Mean +S.E. ) 0.5% OFLX Group -7.9 i 2.8**
BM Group -38.5 + 5.8*
Control Group -15.0 i 5.8 Note: ** P <0.01 vs. GM group * P <0.05 vs. control group As can be seen from Table 2, reduction of acoustic acuity of an average of 15 dB was noted in the control group, while the GM group showed a rise in ABR threshold of 38.5 dB, that lS, remarkable reductlon of acoustic acuity. On the other hand, the 0.5% OFLX group showed an 15~ extremely small rise in ABR threshold, i.e., reduction in auditory acuity, averaging 7.9 dB. Therefore, it was confirmed that ofloxacin did not have any ototoxicity.
ii) SEM Observations on Cochlear Hair Cell;
The SE~ picture of the cochlea in the control group~ or~ 0.5~ OF~X group revealed that the hair of the outer and inner hair cells at the basal turn and the second or third turns suffered form no disturbance.
On the other hand, the SEM picture of the cochlea of the GM group revealed that the outer and inner hair 25 ` cell~ suffered from di turbance of ~he row of the hair .,. - .
," ,. .,.~
1 cells or disappearance of the hair cells fxom the basal -~
turn through the third turn. There was observed a b#,.
tendency that the disturbance of the inner hair cells became serious toward the upward turn. On the other hand, the outer hair cells did not show such a tendency, however, a stronger disturbance o the outer hair cells i ; was noted at the third turn thereof. Also, when SEM was also carried out on 6 ears on the opposite side of the animals of the GM group, a slight disturbance of the outer ~-: .
- 10 hair cells was observed in every case, in spite of that GM
was administered directly to these-ears.
iii) Observations of Middle Ear Mucosa: ~ `
Considerable inflammation, such as remarkable cellular infiltrate in the mucosa or thickening of the ~ 15 mucous periosteum, were observed in the control ~roup. To ;; the contrary, such inflammation was not observed in the middle ear mucosa of the 0.5% OFLX ~roup and the GM group. ~
iv) Distribution of Ofloxacin: -~ The results are shown in Table 3.
;~ ~ 20 ;
. ~ . ...; ~
. : :.:.. : .:
'"''~''`~' ``' ".
.::~ ., ., ~
~ ~
- ~ ~
` :.. ,;'.
~ ' .''~' ';
- 10 - " ,-`''',.. ';
.. .. , . ~: `. ~ ~
$ ~ -:
1 TABhE 3 Concentration of OFLX in Various Tissues After OFLX Admin.
Time Ofloxacin Concen. (~q/me or uq/ql ~-from Mid. Ear No. Admin. Serum Brain Mucosa LYmph (hr) OFLX 1 i-1.5 <0.19 <0.20 78.70<1.00 ~;~
Group 2 " 0.91 <0.20 3 " <0.19 <0.20 4 " <0.19 <0.20 1.5 2~0.19 <0.20 45.853.80 7 " 1.20 <0.20 9 " <0.19 <0.20 " ~0.19 <0.20 6 2-2.5 <0.19 <0.20 40.85<1.00 11 ~l ~0.19 <0.20 12 " 0.19 <0.20 13 " 0.39 <0.20 ::: -. . ~.:
Control 1 <0.20 Group 2 <0.20 ~ ~
As can be seen from Table 3, the ofloxacin ~ `
concentration in the serum was less than 0.19 ~g/m~ in most of the cases of the OFLX group. Therefore, ofloxacin did not distributed to tissues other than the middle ear.
In particular, from the~fact that the concentration of ~;~ - ofloxacin in the brain was less than 0.20 ~g/g in all ~
- 11 - ~ :
~ ' ' '' ;.'"'; ', l cases, the same level in the controls. Therefore, it was considered that side effects on the central nervous system, which are liable to be induced by the use of new quinolone-type antibacterial agents, were not involved at all in case of administration of ofloxacin to the ear. On the other hand, distribution of ofloxacin to the middle ear mucosa, which is of the most important from the standpoint of effectiveness, was higher than 40 ~g/g, ;~ As above demonstrated, ofloxacin, when topically administered into the ear, caused substantially no ototoxicity and exhibited excellent distribution to the desired middle ear mucosa without showing substantially no distribution to tissues, particularly to the brain, other than the desired tissues. Thus, the ofloxacin topical preparations for otopathy according to the present invention are believed to be of extremely high clinical use.
It is known that otitis media and otitis externa ; 20 are induced through bacterial infection. Hence, anti~
~; bacterial activities of ofloxacin on all the bacteria isolated from the lesion of a patient suffering from purulent otitis media were assayed in comparison with other drugs for otopathy. The results obtained were shown in Table 4 below.
,.,,~
' ',:' "'. ':.
- 12 - ~- ~
r ~ ~ ~ ~ 3 :4 IJ~ 13 ~q ,,, C ~ al u .' al ~ .,,.~
~ ~ 8 U.v ~ 8 ~ ~ ~
o o ~ o ~ ~ "
, o ~ al o ~ p,, '' o u .,1 R~
Lq X O ~ o E. ca C) nl Q Ul .¢ ~4 C
U~
r ~ ¦
U o :
sI
æ . .
o~ ~ ~
~ I U U~ :.
E, ., ~.... --I .~ . ;
,J~, nJ '. ~
~ . . .
o E ''~
m ~
.,,.,,",""",.....
: ~ ~
~: 3 ~ ~ ~ ~
O R
Z .
`~ ` 0~
~: ~ bo O
a o-.l ~ ~ o ~ S~
~, ~ a) ~1 s s O X C~ X C) ~ ~ E, ~': '.~ :: `
- 13 - :
As is apparent from Table 4 above, ofloxacin exhibited more excellent antibacterial activities on :~
bacteria causing purulent otitis media than other conventional drugs.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various ~.-changes and modifications can be made therein without departing from the spirit and scope thereof. . --,," ",,,,,, " ~,,,,~, " ':
~: ., .. -~15 ' '," ` -, ~: 20
'.','.";..`.' ~
~...,.:.., ~=~
r~
~ 3 3 ~
1 cavity once a day for consecutive 7 days. ABR was measured after 10 days from the final day of injeation.
2) Result~
The change between the ABR threshold before the administration and that after the administration was shown in Table 1 below.
TABLE 1 . ~
Chanqe of ABR Threshold Threshold (d~, Mean +S.~
Before Admin. After Admin.
0.3% OFLX Group 30 i-1.-3 34.5 i 1.4 Control Group 30 i 1.6 35 ~ 1.6 As is apparent from Table 1, the threshold changes : ~ .
in both of the 0.3% OFLX group and the control group were ~ `~
15slight (4.5 dB and 5.0 dB, respectively), indicating that ~-;~ the reduct1on of acoustic acuity due to the administration -~
of ofloxacin was negligible.
TEST EXAMPLE 2 ~ ;~
1) Test Animal and Administration Route~
20~ Twenty-nine guinea pLgs showing normal Preyer's `~-reflex~Ibody weight: ;250 t~ 350 9) were divided into the following three groups; 12 in a group receiving topical `
administration of 0.5% ofloxacin solution (hereinafter -~
;re~erred to as ll~o.s% OF~X group"); 13 in a group topically 25administered with gentamicin ~hereinafter referred to as :
~ _ 5 _ ~ ~
': . `' , '''.~ "'-` .'."' ~ ~ ~3 ~
1 "GM group"); and 4 in a control group administered with physiological saline.
After ketalar and a muscle relaxant (xylazine) were intramuscularly administere~1, an incision of 2 mm in diameter was made at the middle ear from the posterior portion of the ear of the guinea pig, and a tube of the same diameter was inserted into the tympanic cavity through the opening and sealed and fixed with an adhesive.
- The incision wound was temporarily sutured and closed.-Immediately after the operation, ABR ~as r-ecorded. -From the same day, 0.2 me of a 4% gentamicin solution, 0.2 mC
., ~.,~
of the ofloxacin solution of Example 2, or 0.2 me of the control solution (physiological saline) was injected through the tube into the tympanic cavity. The injection was made once a day for consecutive 10 days. On the 10th day, ABR was again recorded, and the animals were killed. ~ ;
2) ~ethod of Observation:
i) Measurement of ABR: -An ear drum lead was used for the measurement of ABR. The ground electrode was placed on the foreleg of the same side as the injected ear of the guimia pigs. A
clicking sound waB given to the external auditory canal from a tube via a crystal receiver. The auditory response was given as a reaction wave, and an average of 200 measurements obtained by a computer was recorded by an XY
:~ ' '~
- 6 - ~;
3 ~ 5 .
1 recorder. The ABR threshold in the individual animal was obtained from the resulting elec~rocochleogram. ; ;~
ii) Morphological Observation a. Microscopic Observation~
A sample tissue tmiddle ear mucosa) was fixed in - ;
formalin using the auditory bulla in a conventional method. After decalcification, the sample was embedded in paraffine and sliced. The paraffin section was stained ~- with hematoxylin and eosin and microscopi-cally-observed.
:-- - 10 b. Scanning Electronmicroscopic ~EM)~ Observation~
- A sample tissue-(cochlea) was ~horoughly washed in ~;~ a jet stream of physiological 5aline and fixed in a 2.5%
glutaraldehyde solution for 12 hours using a conventional method. Then, the tissue was again washed with a phosphate buffer solution (p~ 7.4) by shaking, fixed in a 1~ osmic acid solution for 1 hour, and electrically .
~ stained with osmium tannate. The tissue was dehyrated ~ .:
with an alcohol using a conventional method and dried at a ~ critical Point, followed by sputtering with platinum ions.
`~ ~ 20 The sample thus prepared was observed under a Hitachi S-570 Model scanning electronmicroscope.
iii) Determination of Distributlon of Ofloxacin Distribution of the drug to the serum, brain tissue, middle ear ;mucosa, and cochlear perilymph was~ ; -~; 25 examined in the control group and the 0.5~ OFLX group. A ~ ~
..: :
... .: .
_ 7 _ ~ - -'~', :,''' , , ,'"'- .'~. '~' ~' ' ~ ~ ~,3~ 'f 1 blood sample was collected ~rom the carotid arteryl and the brain tissue was excised immediately after decapitation. The middle ear mucosa was stripped off after thorough washing of the middle ear cavity with physiological saline. Thereafter, the cochlear perilymph was collected by a glass capillary.
The concentration of the drug in the tissue was biologically assayed according to a paper disc method using B. subtilis ATCC 6051 and E. coli Kp as test micro-organisms.
The serum was used as untreated for the test. The brain tissue was homogenized together with an equal weight of a 0.1M phosphate buffer solution (p~ 7.0) in a glass-, .
made homogenizer to prepare a 50% homogenate solution. ;
Sampling of the perilymph and the middle ear mucosa was carried out within the same time zone, and the ~
samples were pooled in the cold. After measuring the ;
- .
volume of the perilymph the sample was ten-fold diluted ` with a phosphate buffer and tested. On the other hand, ~ .. ..
after weighing and homogenizing, the mucosa sample was tested.
3) Result: -, ~ . , , ., ~ ,. ..
i) Change of Acoustic Acuity: ` `
The change of ABR thresholds are shown in Table 2 below. ~ .~
'. `, ...
,,.:,. ~,,, '`"`.'.'.',".
~:, ::,,.
. ~, ~ 3 ~
., ~ -, ABR Threshold Chanqe Threshold Change ~dB, Mean +S.E. ) 0.5% OFLX Group -7.9 i 2.8**
BM Group -38.5 + 5.8*
Control Group -15.0 i 5.8 Note: ** P <0.01 vs. GM group * P <0.05 vs. control group As can be seen from Table 2, reduction of acoustic acuity of an average of 15 dB was noted in the control group, while the GM group showed a rise in ABR threshold of 38.5 dB, that lS, remarkable reductlon of acoustic acuity. On the other hand, the 0.5% OFLX group showed an 15~ extremely small rise in ABR threshold, i.e., reduction in auditory acuity, averaging 7.9 dB. Therefore, it was confirmed that ofloxacin did not have any ototoxicity.
ii) SEM Observations on Cochlear Hair Cell;
The SE~ picture of the cochlea in the control group~ or~ 0.5~ OF~X group revealed that the hair of the outer and inner hair cells at the basal turn and the second or third turns suffered form no disturbance.
On the other hand, the SEM picture of the cochlea of the GM group revealed that the outer and inner hair 25 ` cell~ suffered from di turbance of ~he row of the hair .,. - .
," ,. .,.~
1 cells or disappearance of the hair cells fxom the basal -~
turn through the third turn. There was observed a b#,.
tendency that the disturbance of the inner hair cells became serious toward the upward turn. On the other hand, the outer hair cells did not show such a tendency, however, a stronger disturbance o the outer hair cells i ; was noted at the third turn thereof. Also, when SEM was also carried out on 6 ears on the opposite side of the animals of the GM group, a slight disturbance of the outer ~-: .
- 10 hair cells was observed in every case, in spite of that GM
was administered directly to these-ears.
iii) Observations of Middle Ear Mucosa: ~ `
Considerable inflammation, such as remarkable cellular infiltrate in the mucosa or thickening of the ~ 15 mucous periosteum, were observed in the control ~roup. To ;; the contrary, such inflammation was not observed in the middle ear mucosa of the 0.5% OFLX ~roup and the GM group. ~
iv) Distribution of Ofloxacin: -~ The results are shown in Table 3.
;~ ~ 20 ;
. ~ . ...; ~
. : :.:.. : .:
'"''~''`~' ``' ".
.::~ ., ., ~
~ ~
- ~ ~
` :.. ,;'.
~ ' .''~' ';
- 10 - " ,-`''',.. ';
.. .. , . ~: `. ~ ~
$ ~ -:
1 TABhE 3 Concentration of OFLX in Various Tissues After OFLX Admin.
Time Ofloxacin Concen. (~q/me or uq/ql ~-from Mid. Ear No. Admin. Serum Brain Mucosa LYmph (hr) OFLX 1 i-1.5 <0.19 <0.20 78.70<1.00 ~;~
Group 2 " 0.91 <0.20 3 " <0.19 <0.20 4 " <0.19 <0.20 1.5 2~0.19 <0.20 45.853.80 7 " 1.20 <0.20 9 " <0.19 <0.20 " ~0.19 <0.20 6 2-2.5 <0.19 <0.20 40.85<1.00 11 ~l ~0.19 <0.20 12 " 0.19 <0.20 13 " 0.39 <0.20 ::: -. . ~.:
Control 1 <0.20 Group 2 <0.20 ~ ~
As can be seen from Table 3, the ofloxacin ~ `
concentration in the serum was less than 0.19 ~g/m~ in most of the cases of the OFLX group. Therefore, ofloxacin did not distributed to tissues other than the middle ear.
In particular, from the~fact that the concentration of ~;~ - ofloxacin in the brain was less than 0.20 ~g/g in all ~
- 11 - ~ :
~ ' ' '' ;.'"'; ', l cases, the same level in the controls. Therefore, it was considered that side effects on the central nervous system, which are liable to be induced by the use of new quinolone-type antibacterial agents, were not involved at all in case of administration of ofloxacin to the ear. On the other hand, distribution of ofloxacin to the middle ear mucosa, which is of the most important from the standpoint of effectiveness, was higher than 40 ~g/g, ;~ As above demonstrated, ofloxacin, when topically administered into the ear, caused substantially no ototoxicity and exhibited excellent distribution to the desired middle ear mucosa without showing substantially no distribution to tissues, particularly to the brain, other than the desired tissues. Thus, the ofloxacin topical preparations for otopathy according to the present invention are believed to be of extremely high clinical use.
It is known that otitis media and otitis externa ; 20 are induced through bacterial infection. Hence, anti~
~; bacterial activities of ofloxacin on all the bacteria isolated from the lesion of a patient suffering from purulent otitis media were assayed in comparison with other drugs for otopathy. The results obtained were shown in Table 4 below.
,.,,~
' ',:' "'. ':.
- 12 - ~- ~
r ~ ~ ~ ~ 3 :4 IJ~ 13 ~q ,,, C ~ al u .' al ~ .,,.~
~ ~ 8 U.v ~ 8 ~ ~ ~
o o ~ o ~ ~ "
, o ~ al o ~ p,, '' o u .,1 R~
Lq X O ~ o E. ca C) nl Q Ul .¢ ~4 C
U~
r ~ ¦
U o :
sI
æ . .
o~ ~ ~
~ I U U~ :.
E, ., ~.... --I .~ . ;
,J~, nJ '. ~
~ . . .
o E ''~
m ~
.,,.,,",""",.....
: ~ ~
~: 3 ~ ~ ~ ~
O R
Z .
`~ ` 0~
~: ~ bo O
a o-.l ~ ~ o ~ S~
~, ~ a) ~1 s s O X C~ X C) ~ ~ E, ~': '.~ :: `
- 13 - :
As is apparent from Table 4 above, ofloxacin exhibited more excellent antibacterial activities on :~
bacteria causing purulent otitis media than other conventional drugs.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various ~.-changes and modifications can be made therein without departing from the spirit and scope thereof. . --,," ",,,,,, " ~,,,,~, " ':
~: ., .. -~15 ' '," ` -, ~: 20
Claims (17)
1. A topical preparation for treating otopathy which contains ofloxacin or a salt thereof and a pharmaceutically acceptable carrier.
2. A topical preparation for treating otopathy which contains an acid addition salt of ofloxacin and a pharmaceutically acceptable carrier.
3. A topical preparation for treating inflammatory otopathy which contains ofloxacin or a salt thereof and a pharmaceutically acceptable carrier.
4. A topical preparation for treating inflammatory otopathy which contains an acid addition salt of ofloxacin and a pharmaceutically acceptable carrier.
5. A topical preparation for treating otopathy which contains ofloxacin or a salt thereof and an aqueous solution as a carrier.
6. A topical preparation for treating otopathy which contains ofloxacin or a salt thereof and an aqueous solution as a carrier, said aqueous solution selected from water, physiological saline and an aqueous buffer solution.
7. A topical preparation for treating otopathy which contains ofloxacin or a salt thereof, an aqueous solution as a carrier, said aqueous solution selected from water, physiological saline and an aqueous buffer solution and an antiseptic.
8. A topical preparation for treating otopathy which contains ofloxacin or a salt thereof, an aqueous solution as a carrier, said aqueous solution selected from water, physiological saline and an aqueous buffer solution and an antiseptic, said antiseptic selected from the group consisting of methyl p-hydroxybenzoate and benzalkonium chloride.
9. A topical preparation for treating otopathy which contains ofloxacin or a salt thereof, an aqueous solution as a carrier, said aqueous solution selected from water, physiological saline and an aqueous buffer solution and an antiseptic, said antiseptic selected from the group consisting of methyl p-hydroxybenzoate and benzalkonium chloride, said preparation having a neutral pH.
10. A topical preparation for treating otopathy which contains from about 0.05 to about 2% w/v of ofloxacin or a salt thereof and an aqueous solution as a carrier.
11. A topical preparation for treating otopathy which contains from about 0.1 to about 1% w/v ofloxacin or a salt thereof and an aqueous solution as a carrier.
12. A topical preparation for treating otitis media which contains ofloxacin or a salt thereof and a pharmaceutically acceptable carrier.
13. A topical preparation for treating otitis externa which contains ofloxacin or a salt thereof and a pharmaceutically acceptable carrier.
14. An ear drop preparation for treating otopathy which contains ofloxacin or a salt thereof and a pharmaceutically acceptable carrier.
15. A preparation for treating otopathy by otic administration which contains ofloxacin or a salt thereof and a pharmaceutically acceptable carrier.
16. A preparation for treating otopathy by otic administration which contains from about 0.05 to about 2%
w/v of ofloxacin or a salt thereof and an aqueous solution as a carrier.
w/v of ofloxacin or a salt thereof and an aqueous solution as a carrier.
17. A preparation for treating otopathy by otic administration which contains from about 0.1 to about 1% w/v ofloxacin or a salt thereof and an aqueous solution as a carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63086378A JPH01258620A (en) | 1988-04-08 | 1988-04-08 | Local pharmaceutical for otopathy |
| JP86378/88 | 1988-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1330946C true CA1330946C (en) | 1994-07-26 |
Family
ID=13885215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000595126A Expired - Lifetime CA1330946C (en) | 1988-04-08 | 1989-03-30 | Topical preparation for treating otopathy containing ofloxacin or a salt thereof |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5401741A (en) |
| EP (1) | EP0337328B1 (en) |
| JP (2) | JPH01258620A (en) |
| KR (1) | KR0126471B1 (en) |
| AT (1) | ATE109350T1 (en) |
| AU (1) | AU614349B2 (en) |
| CA (1) | CA1330946C (en) |
| DE (1) | DE68917186T2 (en) |
| DK (1) | DK175302B1 (en) |
| HK (1) | HK196596A (en) |
| HU (1) | HU00407A9 (en) |
| IE (1) | IE65859B1 (en) |
| IL (1) | IL89807A (en) |
| NZ (1) | NZ228632A (en) |
| PH (1) | PH26367A (en) |
| ZA (1) | ZA892449B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686095A (en) * | 1995-10-23 | 1997-11-11 | Price, Jr.; Francis W. | Method of treating canker sores |
| US5753269A (en) * | 1995-12-27 | 1998-05-19 | Bayer Corporation | Otic microbial combinations |
| US6022551A (en) * | 1998-01-20 | 2000-02-08 | Ethicon, Inc. | Antimicrobial composition |
| US5972358A (en) * | 1998-01-20 | 1999-10-26 | Ethicon, Inc. | Low tack lotion, gels and creams |
| US6248343B1 (en) | 1998-01-20 | 2001-06-19 | Ethicon, Inc. | Therapeutic antimicrobial compositions |
| US5997893A (en) * | 1998-01-20 | 1999-12-07 | Ethicon, Inc. | Alcohol based anti-microbial compositions with cosmetic appearance |
| US5912255A (en) * | 1998-02-27 | 1999-06-15 | Bussell; Letantia | Topical fluoroquinolone antibiotics combined with benzoyl peroxide |
| US6017912A (en) * | 1998-02-27 | 2000-01-25 | Bussell; Letantia | Topical fluoroquinolone antibiotics in an alcohol and acetone vehicle |
| KR100595956B1 (en) * | 1998-08-21 | 2006-07-03 | 센주 세이야꾸 가부시키가이샤 | Aqueous liquid preparations |
| DE19937116A1 (en) * | 1999-08-06 | 2001-02-08 | Bayer Ag | Moxifloxacin saline formulation |
| US7064132B2 (en) * | 1999-11-28 | 2006-06-20 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis external |
| US6156294A (en) * | 1999-11-28 | 2000-12-05 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
| US6676930B2 (en) * | 1999-11-28 | 2004-01-13 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
| JP2004509918A (en) | 2000-09-25 | 2004-04-02 | バイエル・ヘルスケア・エルエルシー | Combination of antimicrobial agents for ear treatment for the treatment of eardrum ruptured animals |
| US20090215735A1 (en) * | 2002-02-25 | 2009-08-27 | Alcon, Inc. | Topical solution formulations containing a corticosteroid and a cyclodextrin |
| US8940321B2 (en) | 2003-12-12 | 2015-01-27 | Otic Pharma Ltd. | Compositions for treatment of ear disorders and methods of use thereof |
| CA2548892C (en) * | 2003-12-12 | 2015-10-27 | Eran Eilat | Compositions for treatment of ear disorders and methods of use thereof |
| US8318817B2 (en) | 2008-07-21 | 2012-11-27 | Otonomy, Inc. | Controlled release antimicrobial compositions and methods for the treatment of otic disorders |
| CN105682742A (en) | 2013-08-27 | 2016-06-15 | 奥德纳米有限公司 | Treatment of pediatric otic disorders |
| US11040004B2 (en) | 2016-09-16 | 2021-06-22 | Otonomy, Inc. | Otic gel formulations for treating otitis externa |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260416A (en) * | 1979-09-04 | 1981-04-07 | Allied Chemical Corporation | Amorphous metal alloy for structural reinforcement |
| JPS5746986A (en) * | 1980-09-02 | 1982-03-17 | Dai Ichi Seiyaku Co Ltd | Pyrido(1,2,3-de)(1,4)benzoxazine derivative |
| US4551456A (en) * | 1983-11-14 | 1985-11-05 | Merck & Co., Inc. | Ophthalmic use of norfloxacin and related antibiotics |
| JPS638333A (en) * | 1986-06-30 | 1988-01-14 | Dai Ichi Seiyaku Co Ltd | External preparation |
| JP2558107B2 (en) * | 1986-12-18 | 1996-11-27 | 第一製薬株式会社 | Topical |
| CA1309024C (en) * | 1986-12-19 | 1992-10-20 | Hiromitsu Seki | Aqueous pharmaceutical composition containing s-(-)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl -7-oxo-2,3,-dihydro-7h-pyridol[1,2,3,-de][1,4]benzoxazine -6-carboxylic acid |
-
1988
- 1988-04-08 JP JP63086378A patent/JPH01258620A/en active Pending
-
1989
- 1989-03-30 CA CA000595126A patent/CA1330946C/en not_active Expired - Lifetime
- 1989-03-30 IL IL89807A patent/IL89807A/en unknown
- 1989-04-03 ZA ZA892449A patent/ZA892449B/en unknown
- 1989-04-06 KR KR1019890004498A patent/KR0126471B1/en not_active IP Right Cessation
- 1989-04-06 NZ NZ228632A patent/NZ228632A/en unknown
- 1989-04-06 PH PH38446A patent/PH26367A/en unknown
- 1989-04-07 DE DE68917186T patent/DE68917186T2/en not_active Expired - Lifetime
- 1989-04-07 IE IE111889A patent/IE65859B1/en not_active IP Right Cessation
- 1989-04-07 AT AT89106215T patent/ATE109350T1/en not_active IP Right Cessation
- 1989-04-07 EP EP89106215A patent/EP0337328B1/en not_active Expired - Lifetime
- 1989-04-07 AU AU32567/89A patent/AU614349B2/en not_active Expired
- 1989-04-07 JP JP1089379A patent/JP2573351B2/en not_active Expired - Lifetime
- 1989-04-07 DK DK198901681A patent/DK175302B1/en not_active IP Right Cessation
-
1993
- 1993-04-12 US US08/048,959 patent/US5401741A/en not_active Expired - Lifetime
-
1995
- 1995-06-22 HU HU95P/P00407P patent/HU00407A9/en unknown
-
1996
- 1996-10-24 HK HK196596A patent/HK196596A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HU00407A9 (en) | 1995-09-28 |
| EP0337328A3 (en) | 1991-12-27 |
| ATE109350T1 (en) | 1994-08-15 |
| IL89807A (en) | 1993-08-18 |
| IE65859B1 (en) | 1995-11-29 |
| IE891118L (en) | 1989-10-08 |
| DK168189D0 (en) | 1989-04-07 |
| PH26367A (en) | 1992-06-01 |
| KR0126471B1 (en) | 1997-12-24 |
| DK175302B1 (en) | 2004-08-16 |
| JP2573351B2 (en) | 1997-01-22 |
| HK196596A (en) | 1996-11-01 |
| JPH0334925A (en) | 1991-02-14 |
| AU3256789A (en) | 1989-10-12 |
| NZ228632A (en) | 1991-10-25 |
| DE68917186D1 (en) | 1994-09-08 |
| AU614349B2 (en) | 1991-08-29 |
| DE68917186T2 (en) | 1995-01-05 |
| US5401741A (en) | 1995-03-28 |
| DK168189A (en) | 1989-10-09 |
| JPH01258620A (en) | 1989-10-16 |
| ZA892449B (en) | 1989-12-27 |
| EP0337328A2 (en) | 1989-10-18 |
| EP0337328B1 (en) | 1994-08-03 |
| KR890015742A (en) | 1989-11-25 |
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