Note: Descriptions are shown in the official language in which they were submitted.
7~
The present invention relates to an antidote which
consists of essentially spherical particles of activated
carbon. The carbon is useful in removing poisonous or
harmful substances from the gastrointestina] tracts, such
as the stomach and intestines.
It has been known for a long time that activated
carbon is effective as a remedy for intestinal troubles
when used internally and is utilized for many thera-
peutical purposes. It has been reported that, when
internally administered, the activated carbon shows
an excellent therapeutical efficacy particularly on
bacterial-infectious diseases such as dysentery, cholera,
typhoid abdominalis, alimentary intoxication, indigestion,
flatus in intestines, chronic gastritis, epilepsy,
dizziness, chlorosis, anthrax and the like. In cases of
undesirable intake of drugs and poison, the first-aid oral
administration of activated carbon produces an antidotal
effect. Furthermore, the internal use of activated carbon
is effective for removing from the gastrointestinal trActs
noxious substances which are ormed due to abnormalities
of metabolism caused by various diseases. These effects
are considered to be due to the fact that toxines,
abnormal metabolites or substances which induce the
formation of such toxines and/or abnormal metabolites in
the gastrointestinal tracts are adsorbed on the activated
carbon, which is completely harmless to living bodies, and
the activated carbon orally administered to living hody
is discharged outside of the body bearing thereon the
above-mentioned noxious substances.
For antidotal purposes, it has hitherto been general
to use powdery activated carbon. In its application, the
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: .
powdery activated carbon is mixed with water to facilitate
its oral administration. Alternatively, the powdery
activated carbon may be shaped into tablets which are
readily broken to powdery pieces in the gastrointestinal
tracts when swallowed and can develop their inherent
ability of adsorption. However, the use of powdery
activated carbon involves a side effect of causing
constipation, thus presenting a serious disadvantage.
Since the activated carbon is generally internally applied
to patients who suffer from various diseases and are thus,
more or less, in a decline, the patients suffer great pain
due to the constipation involved, and in some cases there
may be a danger to life due to the lack of the excreting
ability of the patients unless the feces are mechanically
removed.
It has now been found that essentially spherical
particles of activated carbon comprising at least 85 %,
preferably 90 %, in number of microscopically spherical
particles of activated carbon hereinafter specified does
not exhibit the secondary effect of causing constipation
but shows an excellent antidotal effect.
Thus, according to the invention there is provided
an antidote, which consists essentially of discreté spherical
activated carbon comprising at least 85% in number of
microscopically spherical particles of activated carbon
which have smooth and convex-curved surfaces without
conspicuous edges and a ratio of the maximum diameter
to the minimum diameter of 1.0-1.3, both said essentially
spherical and said microscopically spherical particles of
activated carbon being 0.05 - 2mm in diameter. They
are preferably 500 - 2,000 m2/g in surface area and
0.05 - 1.0 cc/g in volume of
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'
pore cavity determined in the range o~ pore-radius of
100 - 75,000 A.
The essentially spherical particles and the microscop-
ically spherical particles are preferably 0.1 to 1.0 mm in
diameter and preferably have a pore cavity volume of 0.1
to 0.8 cc/g.
The spherical particles of activated carbon with a
size (diameter) smaller than 0.05 mm are not satisfactory
in respect to the secondary e~fect of causing constipation
although they do show an antidotal effect. When the size
is larger than 2 mm, the spheres are hard to administer
orally and the intended level of antidotal efficacy can
not be developed quickly.
The shape of the particles of activated carbon is one
~; of the important factors for attaining the satisfactory
medical efficacy of the present invention. It is
necessary that the particles be essentially spherical, and
moreover, it is necessary that the essentially spherical
particles of activated carbon comprise at least 85 % in
number of microscopically spherical particles of activated
carbon, both particles oE act~vated carbon having the
above-mentioned parameters. That is, the surface area and
; the volume of pore cavity are the important factors in the
simultaneous development of a satisfactory antidotal
efficacy and the suppression of the secondary effect of
causing constipation. If the surface area and the volume
of pore cavity are too small, the adsorbing power becomes
so small that the practically satisfactory level of
antidotal efficacy can not be obtained.
On the contrary, when the surface area and the volume
of pore cavity are larger than those defined hereinabove,
,i72
constipation is undesirably caused although the antidotal
effect is still present. In addition, it is considered
that microscopically spherical activated carbon of such a
larger surface area and volume of pore cavity is reduced
in physical strength, so that it will readily be broken to
pieces during or after internal administration, causing
the side effect of constipation.
According to the practice of the present invention,
the surface area of both the essentially spherical
particles and the microscopically spherical particles of
activated carbon is in the range of 500 - 2000 m2/g,
preferably 700 - 1,500 m2/g, as determined by a com-
mercially available surface area-determining instrument.
The volume of pore cavity is determined by a commerically
available mercury porosimeter and is generaly in the range
of 0.05 - 1.0 cc/g, preferably 0.1 - 0.8 cc/g with
pore-radius of 100 - 75,000 A.
The starting materials for producing the above-
mentioned particles of activated carbon having the above-
mentioned characteristic properties can be any o ~heknown starting materials ~or activated carbon including
sawdust, coal, coconut shell, pitch, organic synthetic
polymers and the like.
These materials can be converted into spherical
particles of activated carbon. For example, spherical
particles of activated carbon can be obtained by a process
which comprises the steps of shaping an above-mentioned
powdery material into small-sized spheres by the use of a
binder such as pitch, heating and baking the spheres for
carbonization thereof in an inert atmosphere at a
temperature of 800 - 1000C, and activating them in an
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atmosphere of steam at a temperature of 900 - 1000C.
Alternatively, a process as described in, for example,
Japanese Patent Puhlication No. 50-18879, may be employed
which comprises shaping pitch in a molten state into
small-sized spheres, oxidizing the spheres to render them
infusible, heating and baking the spheres for carbonizat;on
in an inert atmosphere at a temperature of 800 - 1000C,
and activating the carbon in an inert atmosphere at a
temperature of 900 - 1000C. The latter process is
especially suitable for the production of the spherical
particles of activated carbon according to the present
invention since it can yield spherical particles of
activated carbon having higher sphericity described above,
higher physical strength and smoother surfaces.
As a matter of course, since the spherical particles
of activated carbon are used internally, they must thus
have such a high purity as to be satisfactory from a
viewpoint of safety. For instance, the spherical par-
ticles of activated carbon should pass a purity test as
prescribed in the standard for "Medicinal Carbon" o the
ninth revision of the Parmacopoeia of Japan.
The essentially spherical particles of activated
carbon according to the present invention may be used
internally by any manner ordinarily applied for
conventional activated carbon. Most simply, the
essentially spherical particles of activated carbon are
suspended in drinking water and orally administered.
Alternatively, the essentially spherical particles of
activated carbon may be formulated as tablets of a
suitable Eorm by known techniques. In this case, it is
necessary that the tablets be so Eormulated that they are
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readily broken to pieces of the original spherical form
in the body so as to ensure the desired therapeutical
effect. Still atlernatively, the above-mentioned
particles of activated carbon may be encapsulated in
- cylindrical capsules in the usual manner.
The dose of the essentially spherical particles of
activated carbon is dependent on the stage of disease, the
necessity of emergaency counteraction, etc., and the
particles are generally taken in an amount of 0.5 - 10 g
at a time and three times a day. Administration after or
between meals is preferred but the particles are, of
course, usable at any time in an urgent case.
The fact that the essentially spherical particles
of activated carbon specified as above do not cause
constipation when administered while still exhibiting
the desired antidotal efficacy is totally unexpected.
Although the reason for the effect has not been
elucidated, this is presumably because known powdery
active carbon tends to absorb the stimulants for the
intestines and thus weakens the entero-cinesia and at the
same time is thoroughly mixed with feces, resulting in an
increase of cohesion of the feces to cause constipation.
On the other hand the spherical particles of activated
carbon according to the invention do not serve to increase
the cohesion due to the smoothness of the essentially
spherical surfaces and adsorb the stimulants for the
intestines in a lesser amount, coupled with the advantage
that the spheres give a proper stimulation to the
intestines, th llS not causing constipation.
The present invention will be described by way of
the following Examples, which should not be construed as
limitation of the invention.
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EXAMPLE l: (preparation of particles_of activated carbon)
.
Seven hundred and fifty parts by weight of a pitch
(with a softening point of 190C., a content of
nitrobenzene-insoluble matter of 30 % by weight, and an
H/C atomic ratio of 0.6) obtained by the thermal cracking
of a crude oil, and 250 parts by weight of naphthalene
were placed in a stainless steel-autoclave equipped with
an agitator, and they were mixed and dissolved at 170C.
To the thus formed solution were added 3,000 parts by
weight of an 0.5 % aqueous solution of "Gosenol GH- 17"
(polyvinyl alcohol-based suspending agent, product of
Nippon Synthetic Chemical Industry Co. Ltd.), followed by
violent agitation at 140C. for 3 minutes and then cooling
to room temperature still under agitation to obtain par-
ticles of pitch. After removing most of the water of the
solution by filtration, the particles were immersed in
methanol in an amount of 5 times by weight as much as that
of the particles, and the thus formed slurry was shaken to
remove naphthalene by dissolution in methanol. After
air-drying, the particles were heated in a small-slzed
rotary kiln up to 300C. at a heating rate of 25C./hr
while passing air therein thereby obtaining infusible,
spherical particles. Then the passage of air was stopped
and the temperature of the kiln was raised to 900C for
carbonization while feeding steam to the particles in the
kiln. The kiln temperature was maintained at 900C. so as
to activate the particles. As a result, spherical par-
ticles of activated carbon of high sphericity mentioned
above were obtained having a diameter of 0.07 - l.~ mm.
The three specimens of spherical particles of
activated carbon indicated in Table 1 were those obtained
by sifting the products of the above-mentioned process.
Table 1 Characteristic Properties of Spherical
Particles_of Activated Carbon _ -
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Characteristic Properties Specimen 1 Specimen 2 Specimen 3
particle size (mm) 0.07 - 0.250.25 - 0.6 0.6 - 1.2
surface area (m2/g) 750 1600 1300
volume of pore cavity 0.12 0.38 0.27
(cc/g)*l
adsorption power (mg/g)*2
indole 340 570 455
octopamine 120 210 150
phen~lethanolamine 1~5 380 290
phenylalanine 150 250 195
tryptophane 200 340 250
ratio of number of micro-
scopically spherical par- 95 99 97
ticles to total number of
particles (%) *3
. _ _ . .
Note: *l Determined by a mercury porosimeter
(Porosimetro Model 70, product Oe Carlo Erba Co., Ltd., Italy)
*2 Amount of adsorption determined by the use of an
aqueous solution having a concentration of 20
mg/dl and adjusted to pH 7.4 by means of a
sodium potassium phosphate buffer solution.
*3 Microscopically spherical particles of activated
carbon means that the particles have smooth and
convex curved surface without edges and ratio of
the maximum diameter to the minimum diameter of
1.0 - 1.3.
The adsorptive ability of the specimens was determined
with regard to amines such as indole and octopamine and
abnormally accumulating amino acids in the gastrointestinal
tracts which are presumed to be generated in the body due
to the abnormal metabolism induced by hepatic diseases. It
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will be appreciated that all of the specimens passed the
standard tests such as the identification test, purity
test, weight loss on drying, and residue on ignition of
"Medicinal Carbon" precribed in the Parmacopoeia of Japan
(the ninth revision).
ACUTE TOXICITY TEST
A test was conducted on mice using the specimens
indicated in Table 1. The test results are shown below,
from which it was confirmed that the spherical particles
of activated carbon according to the present invention
were very high in safety even when administered in large
doses.
For the test, commercially available mice of the
ICR-JCL strain (weighing 22 + 1 g) were used and the
particles of activated carbon of Specimens 1 and 3 of
Table 1 were used as they were, except that Specimen 2 was
finely ground. These specimens were, respectively and
forcibly p.o. administered by a stomach tube. One week
after the administration, the mortality of the mice was
observed and LD50 was determined by the Litch~leld-
Wilcoxon's method. The results are shown in Table 2.
One week after the administrat;on, the mice were
killed and autopsied but no specific abnormal findings
were obtained in appearance and internal organs with no
toxic symptoms involved.
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TABLE 2 ACUTE TOXICITY TEST
,
SpecimenRoute Number of Mice LDso(mg/kg)
Specimen l Oral administration 10 ~15,000*
Specimen 2 " 10 >15,000*
Specimen 3 " 10 ~15,000*
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* The dosage of more than 15,000 mg/kg was found to be
experimentally very difficult and so the administration
test was s-topped at the maximum dosage of 15,000 mg/kg.
No case of death was observed at the highest dosage of
15,000 mg/kg.
EXAMPLE 2 (A~TIDOTAL TEST)
Groups of rats of the Wistar strain, weighing
130 - 140g, were used and orally administered with 20
mg/kg of pentobarbital sodium as an aqueous so].ution.
Immediately after the administration, the specimens of
Table 1 and medicinal powdery carbon were respectively
: suspended in water, each of which was orally administered
at the dosage of 200mg/kg to each of the 10 animals of
the test group. For reference, a comparative test was
simultaneously carried out without the administration of
any activated carbon. Then, the ratio of the average
value of the maximum concentration of pentobarbital sodium
in the blood of the rats in each group to that of animals
in the comparative test group was calculated as a removal
rate, with the results shown in Table 3. From the
results, it will be appreciated that all of the tested
specimens of the activated carbon showed a remarkable
antidotal effect.
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TABLE 3 ANTIDOTAL EFFECT OF SPECIMENS OF ACTIVATED CARBON
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Activated Medicinal
Carbon Specimen 1 Specimen 2 Specimen 3 Powdery
Sample Carbon
.
Removal 88.5 96.3 93.1 92.2
Rate t~)
Ninety minutes after the administration of the
activated carbon, the test rats were each anaesthetically
killed and the digestive tract of each rat was removed to
observe the degree of intra-intestinal transfer of the
carbon. That is, the ratio of the transferred distance
of the activated carbon to the over-all length from the
cardia to the end of the rectum was determined as a
transfer rate. As will be apparent from the results shown
in Table 4, the specimens of activated carbon of the
invention indicated in Table 1 are significantly greater
in the transfer rate, thus being less likely to cause
constipation as experienced with the known powdery carbon.
TABLE 4 INTESTINAL TRANSFER RATE OF
SPECIMENS OF ACTIVATED CARBON
._ . . _ _ .".~ .
Activated Medicinal
Carbon Specimen 1 Specimen 2 Specimen 3 Powdery
Sample Carbon
- -
Trans~er
Rate (~) 69.6 71.4 72,5 55 5
EXAMPLE 3 (clinical cases)
Two women, 24 years old and 36 years old respectively,
who had suffered from habitual constipation and pimples on
their faces were given between meals 3g of the medicinal
powdery carbon at a time, three times a day. From the
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third day after the beginning of the treatment, the number
of the pimples was found to be slighly reduced but the
patients were constipated more heavily, complaining of an
increased pain upon evacuation.
Then, the administration of the medicinal powdery
carbon was stopped, and specimen 1 and specimen 3 of
the spherical particles of activated carbon in Table of
Example 1 were respectively administered to the 24 year-
old and the 36 year-old women each at 3g each time, 3
times a day between meals.
In both cases, the number of the pimples was gradually
reduced from the fourth day and the pimples disappeared
substantially one week after the beginning of the admin-
istration. Further, it was reported that symptoms of
constipation were also mitigated with the disappearance
of the pain on evacuation.
EXAMPLE 4 (clinical case)
A man, 42 years old, who had suffered from repeated
constipation and diarrhea about every week was admin-
istered between meals with 5g of medicinal powdery carbonat a time, three- times a day. As a result, he complained
of an increased pain upon evacuation during the period of
the constipation. The use of the powdery carbon was
stopped and 5g of the spherical particles of activated
carbon of specimen 2 indicated in Table 1 of Example 1 was
then administered at a time, three times a day between
meals. One week after the beginning of administration, he
had a regular evacuation with no pain and the symptom of
diarrhea substantially disappeared.
EXAMPLE 5 (clinical case)
A male 59 year old showed acute hepatitic symptoms and
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the impediment of consciousness with a result of a normo
test of less than 10% and at stage IV of coma. A compo-
sition consisting of 100 g of the spherical particles of
activated carbon of specimen 2 in Table 1 of Example 1
30 g of magnesium hydroxide and 60 ml of syrup of lactu-
lose was divided into 6 portions and the injection of the
portions was begun by a naso-oral tube. No aggravation
of the patient's conditions was observed in the course of
injection.
Next day, a blood exchange transfusion of 4,000ml was
carried out and the administration of a recipe consisting
of the spherical particles of activated carbon/magnesium
hydroxide/syrup of lactulose was continued with the result
that the improvement in EEG was recognized after three
days of illness. Thereafter a daily dose of 50 g of the
spherical particles of activated carbon 30 g of magnesium
hydroxide and 30 ml of syrup of lactulose divided into 6
portions was administered. After five days of illness,
the patient was found to be clearly improved in conscious-
ness, being able to talk. The normo test was improved
remarkably to a level of 32% after seven days of illness
no symptom of constipation due to the administration of
the particles of activated carbon according to the present
invention was observed.
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