Note: Descriptions are shown in the official language in which they were submitted.
CA 02259997 1998-12-31
DESCRIPTION
REMEDIES AND PREVENTIVES FOR STOMATITIS
TECHNICAL FIELD
The present invention relates to agents for treating
and preventing stomatitis.
BACKGROUND ART
Stomatitis is caused on the basis of inflammation of
an intraoral mucosa and means a symptom such as erosion,
erythema or ulcer arising on an intraoral mucosa, angulus
oris and/or labia oris. When the stomatitis becomes severe,
it is accompanied by a pain and bleeding and gives a
patient such serious problems that ingestion becomes
difficult .
As causes attacked by stomatitis, severe diseases,
dystrophy, infection with herpes simplex virus and the
like have been well known. However, the mechanism of the
attack has not been yet known.
It has also been known that severe stomatitis is
induced by chemotherapy and radiotherapy for cancer as a
side effect thereof. The stomatitis is one of dose
limiting factors upon the administration of anticancer
agent. In particular, the stomatitis often obliges the
radiotherapy to stop the treatment or change the
therapeutic scheme.
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CA 02259997 1998-12-31
In general, intraoral cleaning, administration of
various vitamin preparations, and the like have heretofore
been conducted for treating stomatitis. In order to treat
stomatitis attendant on chemotherapy and/or radiotherapy
for cancer, it has also been conducted to administer a
mouth wash containing allopurinol or sodium alginate
[Archives of Practical Pharmacy, Vol. 55, No. 1, p. 28
(1995); Japanese Journal of Hospital Pharmacy, Vol. 18,
No. 5, p. 510 (1992); Japanese Journal of Nursing Acts,
Vol. 37, No. 15, p. 44 (1991); The Journal of Japan
Society for Cancer Therapy, Vol. 25, No. 6, p. 1129
(1990); Japanese Journal of Cancer and Chemotherapy, Vol.
16, No. 10, p. 3449 (1989); and Nippon Acta Radiologica,
Vol. 49, No. 8, p. 1047 (1989)].
However, the conventional therapies for stomatitis
have involved such many problems as their improving
effects on the symptoms are weak, and so the effects are
insufficient for severe stomatitis, and it takes a long
time to improve the symptoms.
Accordingly, there has been a demand for development
of an agent which is excellent in therapeutic effect and
capable of achieving treatment for a short period of time.
DTSCLOHURE OF THE INVENTTnN
The present inventors have carried out an extensive
investigation with a view toward solving the above-
described problems. As a result, it has been found that an
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CA 02259997 1998-12-31
L-carnosine zinc salt or L-carnosine-zinc complex, or a
combination of such a compound with sodium alginate is
effective for the treatment and prevention of stomatitis,
and particularly has marked therapeutic and preventive
effects on stomatitis caused by chemotherapy and/or
radiotherapy for cancer as a side effect thereof, thus
leading to completion of the present invention.
According to the present invention, there is thus
provided an agent for treating and preventing stomatitis,
comprising an L-carnosine zinc salt or L-carnosine-zinc
complex as an active ingredient.
According to the present invention, there is also
provided an agent for treating and preventing stomatitis,
comprising an L-carnosine zinc salt or L-carnosine-zinc
complex, and sodium alginate.
According to the present invention, there is further
provided a method of treating stomatitis, which comprises
administering an effective amount of an L-carnosine zinc
salt or L-carnosine-zinc complex.
According to the present invention, there is still
further provided a method of treating stomatitis, which
comprises administering effective amounts of any one of an
L-carnosine zinc salt and an L-carnosine-zinc complex, and
sodium alginate.
According to the present invention, there is yet
still further provided use of an L-carnosine zinc salt or
L-carnosine-zinc complex for the preparation of an agent
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CA 02259997 1998-12-31
for treating and preventing stomatitis.
According to the present invention, there is yet
still further provided use of any one of an L-carnosine
zinc salt and an L-carnosine-zinc complex, and sodium
alginate for the preparation of an agent for treating and
preventing stomatitis.
BEST MODE FOR CARRYING OUT THE INVENTION
The L-carnosine zinc salt or L-carnosine-zinc
complex (hereinafter referred to as zinc L-carnosine),
which is an active ingredient for the agents for treating
and preventing stomatitis according to the present
invention, is a salt or complex composed of L-carnosine
and zinc. It has been known that two types of amorphous
and crystalline forms exist in such a salt or complex
(Japanese Patent Publication Nos. 5367/1991 and
116160/1995). A crystalline L-carnosine-zinc complex (the
international general name: "polaprezinc") is commercially
available as an agent for treating gastric ulcer and is
generally used in clinical treatment therefor.
Besides the anti-peptic ulcer effect (Japanese
Patent Publication Nos. 5367/1991 and 116160/1995),
preventive and therapeutic effects on hepatopathy
(Japanese Patent Publication No. 62299/1992), therapeutic
effect on pancreatitis (Japanese Patent Application Laid-
Open No. 17022/1991), osteogenesis-facilitating effect
(Japanese Patent Application Laid-Open No. 120257/1991),
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CA 02259997 1998-12-31
preventive and therapeutic effects on inflammatory bowel
diseases (Japanese Patent Application Laid-Open No.
69338/1992), etc. have been known as the pharmacological
effects of zinc L-carnosine. However, nothing has been
known about the therapeutic and preventive effect of zinc
L-carnosine on stomatitis.
On the other hand, sodium alginate is a
polysaccharide constituting cell membranes of brown algae,
and is commercially available and in common use in various
preparation forms as an agent for protecting a mucosa and
homostasis.
However, nothing has been known about the fact that
sodium alginate exhibits therapeutic and preventive
effects on stomatitis by using it in combination with zinc
L-carnosine.
The zinc L-carnosine useful in the practice of the
present invention may be either amorphous or crystalline.
Crystalline zinc L-carnosine and amorphous zinc L-
carnosine can be prepared in accordance with the processes
described in Japanese Patent Publication No. 116160/1995
and Japanese Patent Publication No. 5367/1991,
respectively.
The sodium alginate used in the present invention
may also be a marketed product.
The agents for treating and preventing stomatitis
according to the present invention are preferably provided
in the preparation form of a mouth wash or intraoral
CA 02259997 1998-12-31
ointment.
These preparations can be formulated by suitably
selecting in combination proper additives from, for
example, distilled water for injection, purified water,
calcium carboxymethyl cellulose, sodium carboxymethyl
cellulose, lactose, sorbit, mannit, sucrose, corn starch,
crystalline cellulose, lactitol, cellulose derivatives,
gum arabic, tragacanth gum, gelatin, polysorbate 80, talc,
magnesium stearate, water, ethanol, white petrolatum,
glycerol, fat, fatty oils, glycols, higher alcohols such
as stearyl alcohol, plastibase, paraffin, beeswax,
polyoxyethylene hydrogenated castor oil, saccharin, pine
syrup, etc.
The mouth wash preparation is preferably used in the
form of, for example, a suspension, syrup or emulsion.
However, it is more preferably used in the form of the
suspension because zinc L-carnosine is hardly soluble in
water. Such a suspension may also be prepared just before
use by formulating a tablet, powder or granule preparation
from active ingredients in advance, grinding it in a
mortar or by a grinder, adding the ground product to
distilled water for injection or purified water and then
optionally adding an excipeint such as calcium carboxymethyl
cellulose or sodium carboxymethyl cellulose thereto.
The suspension may also be prepared for use by preparing
an aqueous solution of sodium alginate in advance and
adding and incorporating zinc L-carnosine into the aqueous
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solution.
In a clinical treatment, a commercially available
polaprezinc preparation (trade name: "Promac*Granule 15%")
may also be used to prepare a suspension just before use
like the above powder or granule preparation. Besides, a
commercially available liquid preparation of sodium
alginate is used in place of the distilled water for
injection or purified water to prepare a suspension just
before use, whereby the suspension may be used in the
administration of zinc L-carnosine and sodium alginate in
combination.
Among the agents for treating and preventing
stomatitis according to the present invention, the
intraoral ointment preparation can be prepared by suitably
selecting in combination proper additives from plastibase,
white petrolatum, paraffin, polyoxyethylene hydrogenated
castor oil, beeswax, stearyl alcohol and the like, and
heating and melting them to mix. The intraoral ointment
preparation is preferably used for stomatitis arising on
an angulus oris and/or labia oris with more effect.
When zinc L-carnosine and sodium alginate are used
in combination, both components may be mixed into a
preparation, or both components may be formulated into
separate preparations to use them in combination at the
same time. There is no difference in effect between both
cases.
Although two types of amorphous and crystalline
* Trade-mark
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forms exist in zinc L-carnosine, there is no difference in
therapeutic and preventive effects on stomatitis between
them.
The dose of zinc L-carnosine varies according to the
age, weight and morbid state of a patient to be
administered, its therapeutic effect, an administration
method, administration time, the number of times of
administration, and an administration period. When only
zinc L-carnosine is administered, however, it is preferred
that it should be administered 1 to 10 times a day in a
dose of 1 to 150 mg per once, preferably, 2 to 6 times a
day in a dose of 5 to 30 mg per once.
When zinc L-carnosine and sodium alginate are used
in combination, it is preferred that sodium alginate
should be administered in a dose of 25 to 500 mg,
preferably 50 to 300 mg per once together with the above-
described dose of zinc L-carnosine.
The agents for treating and preventing stomatitis
according to the present invention are effective for
stomatitis by any cause of attack, but exhibit an
excellent effect on stomatitis caused by chemotherapy and
radiotherapy for cancer. Examples of anticancer agents
used in the cancer chemotherapy include generally used
agents such as 5-FU, cisplatin, methotrexate,
cyclophosphamide, cytarabine, vincristine, adriamycin and
mytomycin C.
The mouth wash preparation may be either swallowed
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or spat out after keeping it in a mouth to rinse the mouth.
When stomatitis arisen on an angulus oris and/or labia
oris is treated, the intraoral ointment preparation may be
used, or otherwise the mouth wash preparation may be held
on a swab, absorbent cotton or filmy membrane to apply it.
EXAMPLES
The present invention will hereinafter be described
in more detail by the following Examples (Clinical
Examples, Formulation Examples, etc.). However, the
present invention is not limited to these examples. A
production process of a crystalline L-carnosine zinc salt
used in the Examples (Clinical Examples and Formulation
Examples) and a preparation process of a 5~ sodium
alginate solution used therein will be described as
Referential Examples.
Referential Example 1:
Production process of crystalline L-carnosine zinc
salt:
Sodium hydroxide (3.51 g) was dissolved in methanol
(100 ml), and L-carnosine (9.96 g) was added to the
solution to prepare a uniform solution. A solution with
zinc acetate dihydrate (9.67 g) dissolved in methanol (145
ml) was added dropwise over 30 minutes to the uniform
solution. As a result, white precipitate was gradually
formed. After completion of the addition, the mixture was
stirred for 2 hours, left to stand overnight and then
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filtered. The resultant filter cake was then washed with
water (140 ml) and air-dried at 80°C for 5 hours to obtain
a crystalline L-carnosine zinc salt (12.4 g) as white
powdery crystals.
Referential Example 2:
Preparation process of 5~ sodium alginate solution:
Sodium alginate (5 g; product of Wako Pure Chemical
Industries, Ltd.) was added to purified water (100 ml),
and the mixture was stirred until sodium alginate was
dissolved, thereby preparing a 5~ sodium alginate solution.
Examples (Clinical Examples):
The frequency indicated in each example indicates a
symptomatic process and was judged on the basis of the
side effect standard by the Japanese Cancer Association.
The frequency and symptom thereof are as follows, and a
higher frequency indicates a severer symptom.
Frequency Symptom
0: None
1: Pain and erythema
2: Erosion and ulcer
3: Ulcer, capable of ingesting only a
liquid diet
4: Ulcer, accompanied by bleeding.
Example 1:
A breast cancer patient being subjected to
chemotherapy; woman aged 55 years:
The patient, in the oral cavity of which erosion and
CA 02259997 1998-12-31
ulcer had arisen (frequency 2), was got to rinse her mouse
with a suspension (5 ml) obtained by mixing the
crystalline L-carnosine zinc salt (150 mg), distilled
water for injection (100 ml) and sodium carboxymethyl
cellulose (1 g) and stirring the mixture by a mixer, and
then to swallow it. This process was repeated 5 or 6 times
a day. The administration was continuously conducted for 8
days. As a result, the erosion and ulcer arisen on the
intraoral mucosa were completely healed (frequency 0).
Example 2:
An esophageal cancer patient being subjected to
chemotherapy; woman aged 57 years:
The patient, on the intraoral mucosa and angulus
oris of which ulcer had arise, and who had ingested only a
liquid diet (frequency 3), was got to rinse her mouse with
a suspension (5 ml) obtained by mixing the crystalline L-
carnosine zinc salt (450 mg), distilled water for
injection (100 ml), sodium carboxymethyl cellulose (1 g)
and pine syrup (small amount) and stirring the mixture by
a mixer, and then to spit it out. This agent was
administered 2 to 4 times a day continuously for 6 days.
Thereafter, the amount of an anticancer agent was
increased for 2 days. As a result, the above symptom was
worsened. Accordingly, the same administration as
described above was conducted for 3 days, and the agent
was applied to the angulus oris with a swab for additional
2 days. As a result, the ulcer arisen on the intraoral
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mucosa and angulus oris was completely healed, and the
patient became able to ingest a solid diet (frequency 0).
Example 3:
An acute myelocytic leukemia patient being subjected
to chemotherapy; woman aged 54 years:
The patient, on the intraoral mucosa of which ulcer
had arise, and who had ingested only a liquid diet
(frequency 3), was got to rinse her mouse with a
suspension (5 ml) obtained by mixing the crystalline L-
carnosine zinc salt (300 mg), purified water (100 ml) and
sodium carboxymethyl cellulose (1 g) and stirring the
mixture by a mixer, and then to swallow it. This process
was repeated twice a day. The administration was
continuously conducted for 10 days. As a result, the ulcer
arisen on the intraoral mucosa was completely healed, and
the patient became able to ingest a solid diet (frequency
0).
Example 4:
An acute myelocytic leukemia patient being subjected
to chemotherapy; man aged 24 years:
The patient, who had been difficult to speak because
stomatitis had arisen on both molar gingival sides and
sides of his tongue (frequency 1), was got to rinse his
mouse with a suspension (5 ml) obtained by adding the
crystalline L-carnosine zinc salt (150 mg) to the 5~
sodium alginate solution (100 ml) and stirring the mixture
by a mixer, and then to swallow it. This process was
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repeated 5 or 6 times a day. On the next day the treatment
had been started, pain was relieved and the patient became
able to speak without difficulty. After the administration
was continuously conducted for 11 days, the stomatitis was
completely healed (frequency 0).
Example 5:
A postoperative patient of gastric cancer being
subjected to chemotherapy; man aged 65 years:
The patient, on the angulus oris and labia oris of
which erosion and ulcer had arisen (frequency 2), was got
to rinse his mouse with a suspension (5 ml) obtained by
grinding allopurinol (100 mg) in a mortar, adding the 5~
sodium alginate solution (100 ml) to the ground product
and then stirring the mixture by a mixer, and then to
swallow it. This process was repeated 3 times a day for 9
days. However, pain was not removed (frequency 1). Thus,
the patient was got to rinse his mouth with a suspension
(5 ml) obtained by adding the crystalline L-carnosine zinc
salt (150 mg) to the 5~ sodium alginate solution (100 ml)
and stirring the mixture by a mixer, and then to swallow
it. This process was repeated 3 times a day for 7 days.
As a result, the erosion and ulcer arisen on the angulus
oris and labia oris were completely healed, and at the
same time pain was banished (frequency 0).
Example 6:
A breast cancer patient being subjected to
chemotherapy; woman aged 46 years:
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The patient, in the oral cavity of which blister had
arisen (frequency 2), was got to rinse her mouse with a
suspension (5 ml) obtained by mixing allopurinol (100 mg)
with the 5~ sodium alginate solution (100 ml) 5 times a
day, and then to swallow it. This treatment was conducted
for 8 days. However, the symptom was not improved. Thus,
the patient was got to rinse her mouth with a suspension
(5 ml) obtained by adding the crystalline L-carnosine zinc
salt (150 mg) to the 5~ sodium alginate solution (100 ml)
and stirring the mixture by a mixer, and then to swallow
it. This process was repeated 5 times a day for 5 days.
As a result, the blister in the oral cavity completely
disappeared (frequency 0).
Example 7:
An esophageal cancer patient being subjected to
chemotherapy; man aged 65 years:
The patient, in the oral cavity of which ulcer
accompanied by bleeding had arisen (frequency 4), was got
to rinse his mouse with a suspension (5 ml) obtained by
adding the crystalline L-carnosine zinc salt (150 mg) and
sodium alginate (5 g) to purified water (100 ml) and
stirring the mixture by a mixer, and then to swallow it.
This process was repeated 5 times a day for 11 days. As a
result, the bleeding was stopped, and the ulcer was
completely healed (frequency 0).
Example 8:
A rectum cancer patient being subjected to both
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CA 02259997 2004-12-23
radiotherapy and chemotherapy; man aged 81 years:
A proper amount of a suspension obtained by adding
the crystalline L-carnosine zinc salt (150 mg) to the 5%
sodium alginate solution (100 ml) and stirring the mixture
by a mixer was soaked into a swab to apply the suspension
to the affected part of the patient who had suffered from
angular bleeding (frequency 2). This process was repeated
or 6 times a day for 3 days. As a result, the angular
bleeding was completely stopped (frequency 0).
Example 9:
An acute leukemia patient being subjected to
chemotherapy; woman aged 25 years:
The patient, on the angulus oris and labia oris of
which erosion and ulcer had arisen (frequency 2), was got
to rinse her mouse with a suspension (5 ml) obtained by
s grinding 1 g (containing 150 mg of polaprezinc) of "Promac*
Granule l5%" (product of ZERIA PHARMACEUTICAL CO., LTD.)
in a mortar, adding the ground product to an Alloid G
solution (100 ml) (5% sodium alginate,.solution; product of
Kyosei Seiyaku K.K. and KAIGEN CO., LTD.) and then
stirring the mixture by a mixer, and then to spit it out.
This process was repeated 3 times a day for 37 days. As a
result, the erosion and ulcer arisen on the angulus oris
and labia oris were completely healed (frequency 0).
Example 10:
A breast cancer patient being subjected to
chemotherapy; woman aged 61 years:
* Trade-mark
CA 02259997 1998-12-31
The patient, on the angulus oris and labia oris of
which erosion and ulcer had arisen (frequency 2), was got
to rinse her mouse with a suspension (5 ml) obtained by
adding the crystalline L-carnosine zinc salt (150 mg) to
the 5~ sodium alginate solution (100 ml) and stirring the
mixture by a mixer, and then to spit it out. This process
was repeated 3 times a day for 10 days. As a result, the
erosion and ulcer arisen on the angulus oris and labia
oris were almost banished (frequency 1).
Example 11:
A rectum cancer patient being subjected to
radiotherapy; man:
The patient, on the angulus oris and in the oral
cavity of which ulcer accompanied by bleeding had arisen
(frequency 4), was got to rinse his mouse with a
suspension (5 ml) obtained by adding the crystalline L-
carnosine zinc salt (150 mg) to the 5~ sodium alginate
solution (100 ml) and stirring the mixture by a mixer, and
then to spit it out. This process was repeated 3 times a
day for 17 days. As a result, the ulcer and bleeding on
the angulus oris and in the oral cavity were completely
healed (frequency 0).
Example 12:
An esophageal cancer patient being subjected to
chemotherapy; man aged 64 years:
A proper amount of an ointment obtained by adding
and incorporating the crystalline L-carnosine zinc salt
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CA 02259997 1998-12-31
(150 mg) into plastibase (100 g) was held on a swab to
apply it to the affected part of the patient, on the
angulus oris and labia oris of which ulcer had arise, and
who had ingested only a liquid diet (frequency 3). This
process was repeated 3 to 5 times a day for 9 days. As a
result, the ulcer in the oral cavity was completely healed,
and the patient became able to ingest a solid diet
(frequency 0).
Control Example: (Single administration of sodium
alginate)
An esophageal cancer patient being subjected to
chemotherapy; woman aged 61 years:
The patient, in the oral cavity of which erosion and
ulcer had arisen (frequency 2), was got to rinse her mouse
with the 5~ sodium alginate solution (10 ml), and then
swallow it. This process was repeated 3 to 6 times a day
for 7 days. However, the ulcer was not improved at all
(frequency 2).
Example 13
An esophageal cancer patient (man aged 45 years) was
got to rinse his mouse with a suspension (5 ml) obtained
by adding the crystalline L-carnosine zinc salt (150 mg)
to the 5~ sodium alginate solution (100 ml) and stirring
the mixture by a mixer, and then to swallow it. After this
process was conducted 5 times a day, cancer chemotherapy
was started. During the cancer chemotherapy (5 days) and
up to the day following the completion of the therapy, the
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CA 02259997 1998-12-31
mouth rinsing was continued 3 to 4 times a day with the
same crystalline L-carnosine zinc salt-5~ sodium alginate
solution mixture as described above. As a result, the
patient was not attacked by stomatitis at all.
Acute toxicity:
(1) The LDso value of the crystalline L-carnosine zinc
salt was 8,441 mg/kg as determined by oral
administration to rats.
(2) The LDSo value of the sodium alginate was 5,000 mg/kg
as determined by oral administration to rats.
(Formulation Examples)
Example 14:
The crystalline L-carnosine zinc salt (150 mg) was
added to distilled water for injection (100 ml), and
sodium carboxymethyl cellulose (1 g) was further added
thereto. The resultant mixture was stirred by a mixer to
obtain a suspension preparation.
Example 15:
The crystalline L-carnosine zinc salt (150 mg) and
sodium alginate (5 g) were added to purified water (100
ml), and sodium carboxymethyl cellulose (1 g) was further
added thereto. The resultant mixture was stirred by a
mixer to obtain a suspension preparation.
Example 16:
The crystalline L-carnosine zinc salt (150 mg) and
sodium alginate (5 g) were added to distilled water for
injection (100 ml), and sodium carboxymethyl cellulose (1
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CA 02259997 1998-12-31
t
g) was further added thereto. The resultant mixture was
stirred by a mixer to obtain a suspension. This suspension
was incorporated into white petrolatum (100 g) to obtain
an intraoral ointment preparation.
Example 17:
The crystalline L-carnosine zinc salt (300 mg) was
added to plastibase (3 g), and the resultant mixture was
mixed at ordinary temperature to obtain an intraoral
ointment preparation.
INDUSTRIAL APPLICABILITY
The agents for treating and preventing stomatitis
according to the present invention, which comprise zinc L-
carnosine or zinc L-carnosine, and sodium alginate, have
marked therapeutic and preventive effects on stomatitis,
in particular, severe stomatitis caused by chemotherapy
and radiotherapy for cancer. They are extremely high in
safety because of their low toxicity and thus useful as
agents for treating and preventing stomatitis.
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